Submissions for variant NM_000303.3(PMM2):c.422G>A (p.Arg141His)

gnomAD frequency: 0.00338  dbSNP: rs28936415

Total submissions: 57

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078590	SCV000230903	pathogenic	not provided	2015-11-11	criteria provided, single submitter	clinical testing
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000008145	SCV000236521	pathogenic	PMM2-congenital disorder of glycosylation	2015-02-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000078590	SCV000321929	pathogenic	not provided	2019-11-11	criteria provided, single submitter	clinical testing	One of the most common pathogenic PMM2 variants reported among European individuals with CDG-1a (Kjaergaard et al., 2001), but has only been identified in the compound heterozygous state and is predicted to be homozygous lethal (Freeze and Westpahl, 2001); Published functional studies demonstrate a damaging effect with reduced enzyme stability and catalytic activity below detection limits (Vega et al., 2011); This variant is associated with the following publications: (PMID: 25192236, 20981092, 31902100, 28373276, 28940310, 22975760, 10700701, 25333069, 21228398, 11530212, 9140401, 19357119, 11517108, 11589167, 21541725, 27053713, 28139241, 26488408, 23988505, 25108116, 26014514, 16376131, 18629883, 19165618, 28425223, 28566178, 28820871, 30609409, 30487145, 30991241, 31474318, 31391289, 31628766, 31981409, 31980526, 32595772, 32581362, 32064623, 31589614, 33163565, 32874916, 31736265, 33643843, 33204593, 33413482)
Illumina Laboratory Services, Illumina	RCV000008145	SCV000399674	pathogenic	PMM2-congenital disorder of glycosylation	2018-04-24	criteria provided, single submitter	clinical testing	The PMM2 c.422G>A (p.Arg141His) missense variant is well-documented as the most common pathogenic variant found in patients with PMM2-associated congenital disorders of glycosylation (also known as CDG-1a) (Sparks et al. 2015). The p.Arg141His variant was first described by Matthijs et al. (1997) in a group of 33 unrelated individuals with confirmed phosphomannomutase deficiency. In this study, the p.Arg141His variant was identified in a compound heterozygous state in ten affected individuals. A review by Matthijs et al. (2000) looking at over 249 patients from six different studies and 23 different countries concluded that the p.Arg141His variant accounts for 37 percent of all disease-associated alleles. This variant is typically observed in a compound heterozygous state in patients with severe phenotypes and has never been reported in a homozygous state (Sparks et al. 2015). When expressed in vitro, the residual activity of the p.Arg141His recombinant protein is almost zero and thus supports the inference that homozygosity for this mutation is lethal early in development. This variant also shows a decreased binding affinity for the normal substrate and results in a significantly less stable protein compared to wild type (Pirard et al. 1999). The p.Arg141His variant is frequent in most populations and is reported at a frequency of 0.02756 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence the p.Arg141His variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000078590	SCV000511512	pathogenic	not provided	2017-02-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000008145	SCV000611238	pathogenic	PMM2-congenital disorder of glycosylation	2022-04-05	criteria provided, single submitter	clinical testing
Invitae	RCV000008145	SCV000633725	pathogenic	PMM2-congenital disorder of glycosylation	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 141 of the PMM2 protein (p.Arg141His). This variant is present in population databases (rs28936415, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with PMM2-CDG (PMID: 9497260, 11517108, 19357119, 21541725, 25355454). It is commonly reported in individuals of European ancestry (PMID: 9497260, 11517108, 19357119, 21541725, 25355454). ClinVar contains an entry for this variant (Variation ID: 7706). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMM2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic.
Centre for Arab Genomic Studies, Sheikh Hamdan Award for Medical Sciences	RCV000008145	SCV000693883	pathogenic	PMM2-congenital disorder of glycosylation	2017-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000008145	SCV000696497	pathogenic	PMM2-congenital disorder of glycosylation	2021-11-06	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.422G>A (p.Arg141His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 192974 control chromosomes. c.422G>A has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, Matthijs_1997, Barone_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of PMM2 enzyme activity in one study (example, Vega_2011) and an oligomerization profile with a predominant aggregate fraction, less dimerization, nearly non-detectable enzymatic activities, and shorter degradation time in another study (example, Yuste-Checa_2015). Thus, variant severly affected both the folding as well as catalytic properties of the PMM2 protein . Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000008145	SCV000711768	pathogenic	PMM2-congenital disorder of glycosylation	2024-03-21	criteria provided, single submitter	clinical testing	The p.Arg141His variant in PMM2 has been reported in several compound heterozygous individuals with congenital disorder of glycosylation type Ia and is one of the most frequent pathogenic variants in patients with this disorder (Matthijs 1997 PMID: 9140401, Matthijs 1998 PMID: 9497260, de Lonlay 2001 PMID: 11134235). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 7706) and has been identified in 0.7% (472/61238) of Finnish chromosomes and 0.6% (6521/1152934) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide evidence that this variant causes complete loss of enzyme activity (Vega 2011 PMID: 21541725, Andreotti 2015 PMID: 26488408). The p.Arg141His variant has never been observed in homozygosity, suggesting that the total absence of PMM2 activity is not compatible with life (Matthijs 1998 PMID: 9497260). Computational prediction tools and conservation analyses suggests that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital disorder of glycosylation type Ia. ACMG/AMP Criteria applied: PM3_Very Strong, PS3_Moderate, PP4, PP3.
Ambry Genetics	RCV000624874	SCV000741460	pathogenic	Inborn genetic diseases	2021-05-13	criteria provided, single submitter	clinical testing	The c.422G>A (p.R141H) alteration is located in coding exon 5 of the PMM2 gene. This alteration results from a G to A substitution at nucleotide position 422, causing the arginine (R) at amino acid position 141 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the PMM2 c.422G>A alteration was observed in 0.4% (891/224,376) of total alleles studied, with a frequency of 0.84% (177/21,196) in the European (Finnish) subpopulation. This missense alteration is the most frequent disease-causing PMM2 alteration and has been reported in several populations (Matthijs, 1997; Schollen, 2000; Vuillaumier-Barrot, 2000; Bohles, 2001; Quelhas, 2006). While the p.R141H alteration has been reported in compound heterozygosity with a second alteration in numerous patients with PMM2-related congenital disorder of glycosylation, no patients homozygous for this alteration have been reported, likely because it is a severe mutation and homozygosity would be lethal early in development (Matthijs, 1999). This amino acid position is highly conserved in available vertebrate species. The p.R141 amino acid is a crucial part of the distal phosphate binding site in the cap domain of α-PMM2, and loss of the positive charge at this location would impair substrate binding (Silvaggi, 2006). Functional analysis demonstrated that the PMM2 protein product harboring the p.R141H alteration has no residual enzymatic activity when expressed in vitro. Further, the p.R141H protein product had a shortened half-life compared to wild type protein, suggesting that the alteration affects protein stability (Vega, 2011). The p.R141H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000008145	SCV000743895	pathogenic	PMM2-congenital disorder of glycosylation	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000008145	SCV000745326	pathogenic	PMM2-congenital disorder of glycosylation	2017-09-14	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000008145	SCV000745882	pathogenic	PMM2-congenital disorder of glycosylation	2017-02-12	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000008145	SCV000996184	pathogenic	PMM2-congenital disorder of glycosylation	2018-08-13	criteria provided, single submitter	clinical testing	This variant is found in the compound heterozygous state in approximately 40% of individuals with Congenital disorder of glycosylation Type 1A of European ancestry (PMID: 20301289). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.39% (891/224376). The c.422G>A (p.Arg141His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Functional characterization in multiple studies indicates that the p.Arg141His variant negatively impacts protein function including stability and enzymatic activity (PMID: 21541725, 26488408, 26014514). Based on the available evidence, the c.422G>A (p.Arg141His) variant is classified as Pathogenic.
Pediatric Metabolic Diseases, Hacettepe University	RCV000008145	SCV000998567	pathogenic	PMM2-congenital disorder of glycosylation		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000008145	SCV001163402	pathogenic	PMM2-congenital disorder of glycosylation	2024-03-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000008145	SCV001194031	pathogenic	PMM2-congenital disorder of glycosylation	2019-12-19	criteria provided, single submitter	clinical testing	NM_000303.2(PMM2):c.422G>A(R141H) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Please note that in the homozygous state, R141H may be associated with fetal demise. Sources cited for classification include the following: PMID 11058895, 9497260, 10854097, 21541725, 9781039, 26488408, 15844218, 10922383, 26014514, and 10386614. Classification of NM_000303.2(PMM2):c.422G>A(R141H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000078590	SCV001247655	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	PMM2: PM3:Very Strong, PM2, PS3:Supporting
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000008145	SCV001251487	pathogenic	PMM2-congenital disorder of glycosylation		criteria provided, single submitter	research	The PMM2 c.422G>A (p.R141H) pathogenic variant has previously been reported in the compound heterozygous state in congenital disorder of glycosylation type Ia, also called PMM2-congenital disorder of glycosylation (PMM2-CDG) (PMID: 9140401; 9497260; 9781039; 11058895; 11134235; 11517108).
Centogene AG - the Rare Disease Company	RCV000008145	SCV001426499	pathogenic	PMM2-congenital disorder of glycosylation		criteria provided, single submitter	clinical testing
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000008145	SCV001435294	pathogenic	PMM2-congenital disorder of glycosylation	2020-04-02	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000008145	SCV001448754	pathogenic	PMM2-congenital disorder of glycosylation	2019-11-18	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV000008145	SCV001519164	pathogenic	PMM2-congenital disorder of glycosylation	2021-01-04	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000078590	SCV001712854	pathogenic	not provided	2022-02-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000008145	SCV001810578	pathogenic	PMM2-congenital disorder of glycosylation	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000008145	SCV002018869	pathogenic	PMM2-congenital disorder of glycosylation	2023-06-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000008145	SCV002072517	pathogenic	PMM2-congenital disorder of glycosylation	2022-01-06	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PM5_SUP,PP3
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000008145	SCV002512215	pathogenic	PMM2-congenital disorder of glycosylation	2021-10-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
DASA	RCV002255089	SCV002526393	pathogenic	Congenital disorder of glycosylation type I	2022-06-10	criteria provided, single submitter	clinical testing	The c.422G>A;p.(Arg141His)missense change one of most frequently variant associated with the phenotype described in the gene and ClinVar contains an entry for this variant (ClinVar ID: 7706; PMID: 32860008; 32581362; 31474318; 28940310; 28373276; 25333069; 22975760; 21228398; 19357119; 11530212; 10700701; 9140401) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21541725, 26488408, 26014514) - PS3. The variant is present at low allele frequencies population databases (rs28936415– gnomAD 0.03660%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg141His) was detected in trans with a Pathogenic variant (PMID: 9140401; 9497260; 9781039; 11058895; 11134235; 11517108; 19357119; 20301289; 21541725; 25355454) - PM3_very strong. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (c.421C>T (p.Arg141Cys) - PMID: 15844218) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
Genetics and Molecular Pathology, SA Pathology	RCV000008145	SCV002557015	pathogenic	PMM2-congenital disorder of glycosylation	2021-05-10	criteria provided, single submitter	clinical testing	The PMM2 c.422G>A variant is classified as PATHOGENIC (PM3, PP3, PS3, PS4) The PMM2 c.422G>A variant is a single nucleotide change in exon 5 of the PMM2 gene, which is predicted to change the amino acid arginine at position 141 in the protein to histidine. This is a recurrent variant and one of the most common PMM2 mutations (PS4). It is predicted to be homozygous lethal, so is only found in compound heterozygous state (PM3). Functional studies have demonstrated reduced enzyme stability and catalytic activity compared with wild type (PMID:21541725) (PS3). This variant is in dbSNP (rs28936415) and has been reported in population databases (gnomAD 891/224376 alleles, 0 homozygotes). This variant has been reported in ClinVar as pathogenic by multiple other diagnostic laboratories (ClinVar Variation ID: 22745). It is also classed as damaging for congenital disorder of glycosylation type 1a in HGMD (CM971228). Computational predictions support a deleterious effect on the gene or gene product (PP3).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000008145	SCV002766670	pathogenic	PMM2-congenital disorder of glycosylation	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Ia (MIM#212065). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 – This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (891 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated eukaryotic phosphomannomutase domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg141Cys) variant has been classified as likely pathogenic by multiple clinical diagnostic laboratories (ClinVar). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been consistently classified as pathogenic by multiple clinical diagnostic laboratories and is the most common PMM2 pathogenic variant in Northern Europeans (ClinVar, GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
3billion	RCV000008145	SCV003841397	likely pathogenic	PMM2-congenital disorder of glycosylation	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.397%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007706). A different missense change at the same codon (p.Arg141Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000550780). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000008145	SCV003920332	pathogenic	PMM2-congenital disorder of glycosylation	2022-10-13	criteria provided, single submitter	clinical testing	This variant has been reported in the literature as a compound heterozygote in several individuals with Congenital disorder of glycosylation type Ia (CDG-Ia) and segregating with disease in affected family members. Of note, at least one publication notes that this variant is the most common pathogenic variant for this condition (Selected publications: Matthijs 1997 PMID:9140401, van Ommenn 2000 PMID:10700701, Briones 2001 PMID:11589167, Kjaergard 2001 PMID:11517108, Barone 2008 PMID:18629883, Vega 2011 PMID:21541725, Bastaki 2018 PMID:28940310). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.7% (82/10618) (https://gnomad.broadinstitute.org/variant/16-8811153-G-A?dataset=gnomad_r3). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic (Variation ID:7706). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In addition, functional studies support that this variant will impact the protein by affecting folding and catalytic activity (Vega 2011 PMID:21541725, Yuste-Checa 2015 PMID:26014514). In summary, this variant is classified as pathogenic based on the data above.
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV000008145	SCV003920793	pathogenic	PMM2-congenital disorder of glycosylation	2023-04-27	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003924813	SCV004739486	pathogenic	PMM2-related disorder	2023-12-06	criteria provided, single submitter	clinical testing	The PMM2 c.422G>A variant is predicted to result in the amino acid substitution p.Arg141His. This variant has been documented as causative for autosomal recessive congenital disorder of glycosylation type Ia (CDG-Ia), and is one of the most frequent pathogenic variants reported in the PMM2 gene (Matthijs et al. 1997. PubMed ID: 9140401; Kjaergaard et al. 2001. PubMed ID: 11517108; Vega et al. 2011. PubMed ID: 21541725). The c.422G>A (p.Arg141His) variant is also reported as c.425G>A (p.Arg141His) in the literature. Functional in vitro studies on this variant have demonstrated that it severely impacts protein stability and activity (Vega et al. 2011. PubMed ID: 21541725). Additionally, a mouse model (compound heterozygous for variants corresponding to the human p.Arg141His and p.Phe119Leu variants) demonstrated prenatal death and significantly stunted growth in animals due to protein glycosylation deficiencies (Chan et al. 2016. PubMed ID: 27053713). Of note, the c.422G>A variant has been observed with a subpopulation (European) frequency up to ~0.8% in a large database of individuals with unknown phenotype. However, no homozygotes have been reported to date, and the c.422G>A (p.Arg141His) variant is suspected to be embryonically lethal when present in the homozygous state (Matthijs et al. 1998. PubMed ID: 9497260; Thiel et al. 2006. PubMed ID: 16847317). This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/7706/). Taken together, we interpret this variant as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000008145	SCV004810049	pathogenic	PMM2-congenital disorder of glycosylation	2024-04-04	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000008145	SCV005047051	pathogenic	PMM2-congenital disorder of glycosylation	2024-05-06	criteria provided, single submitter	clinical testing	A PMM2 c.422G>A (p.Arg141His) variant was identified in a heterozygous state. This variant has been reported in numerous individuals with PMM2-related congenital disorders of glycosylation (Matthijs G et al., PMID: 9497260; Kjaergaard S et al., PMID: 11517108; Romano S et al., PMID: 19357119; Vega AI et al., PMID: 21541725; Barone R et al., PMID: 25355454; Matthijs G et al., PMID: 9140401; de Lonlay P et al., PMID: 11134235) and is one of the most frequent pathogenic variants in this gene. The PMM2 c.422G>A (p.Arg141His) variant has been reported in the ClinVar database as pathogenic by several submitters (ClinVar ID: 7706). The global population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.4%, which is consistent with the carrier frequency for this disorder based on the recent estimated incidence of disease (Pajusalu S et al., PMID: 34447415). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PMM2 function. In support of this prediction, functional studies show that the p.Arg141His variant affects protein stability, indicating that this variant impacts protein function (Vega AI et al., PMID: 21541725; Yuste-Checa P et al., PMID: 26014514). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000008145	SCV005051939	pathogenic	PMM2-congenital disorder of glycosylation	2024-02-01	criteria provided, single submitter	curation
OMIM	RCV000008145	SCV000028350	pathogenic	PMM2-congenital disorder of glycosylation	2007-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000008145	SCV000040585	not provided	PMM2-congenital disorder of glycosylation		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000008145	SCV000733550	pathogenic	PMM2-congenital disorder of glycosylation		no assertion criteria provided	clinical testing
Dobyns Lab, Seattle Children's Research Institute	RCV000008145	SCV000916324	pathogenic	PMM2-congenital disorder of glycosylation	2019-02-18	no assertion criteria provided	research
Reproductive Health Research and Development, BGI Genomics	RCV000991177	SCV001142455	pathogenic	Congenital disorder of glycosylation	2020-01-06	no assertion criteria provided	curation	NM_000303.2:c.422G>A in the PMM2 gene has an allele frequency of 0.008 in European(Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that p.Arg141His has reduced protein stability and enzymatic activity in vitro (PMID: 26014514).It was detected in multiple individuals with autosomal recessive PMM2-CDG, compound heterozygous with c.710C>T (p.Thr237Met), c.484C>T (p.Arg162Trp), c.722G>C (p.Cys241Ser), c.677C>G (p.Thr226Ser) (PMID: 21541725).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PM3_Strong; PS3; PP4
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003989	SCV001162015	likely pathogenic	Congenital cerebellar hypoplasia; Cerebellar ataxia; Muscular dystrophy; Diabetes mellitus		no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003990	SCV001162016	likely pathogenic	Cerebellar ataxia		no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003991	SCV001162017	pathogenic	Congenital cerebellar hypoplasia; Cerebellar ataxia; Cerebral palsy; Cerebral atrophy; Spasticity; Poor speech		no assertion criteria provided	research
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000008145	SCV001432387	pathogenic	PMM2-congenital disorder of glycosylation		no assertion criteria provided	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001257998	SCV001434811	likely pathogenic	Congenital cerebellar hypoplasia		no assertion criteria provided	research
Natera, Inc.	RCV000008145	SCV001457174	pathogenic	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000078590	SCV001554206	pathogenic	not provided		no assertion criteria provided	clinical testing	The PMM2 p.R141H is one of the most frequent pathogenic variants found to cause congenital disorder of glycosylation type 1a (CDG1a) and is reported in ~40% of European CDG1a cases. This variant has only been found in the compound heterozygous state, suggesting that homozygosity for the p.A141H variant would be lethal (Matthijs_1998_PMID:9497260; Kjaergaard_1998_PMID:9781039). The variant was identified in dbSNP (ID: rs28936415) and ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics, Laboratory for Molecular Medicine, Genetic Services Laboratory, University of Chicago and 15 other laboratories). The variant was identified in control databases in 891 of 224376 chromosomes at a frequency of 0.003971 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 177 of 21196 chromosomes (freq: 0.008351), Ashkenazi Jewish in 71 of 9376 chromosomes (freq: 0.007573), European (non-Finnish) in 511 of 94084 chromosomes (freq: 0.005431), Other in 27 of 6220 chromosomes (freq: 0.004341), Latino in 64 of 30676 chromosomes (freq: 0.002086), South Asian in 24 of 25492 chromosomes (freq: 0.000942), African in 15 of 20700 chromosomes (freq: 0.000725), and East Asian in 2 of 16632 chromosomes (freq: 0.00012). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.R141 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. Functional studies have demonstrated loss of PMM2 protein activity from the p.R141H variant (Vega_2011_PMID:21541725; Yuste-Checa_2015_PMID:26014514). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
GenomeConnect - Invitae Patient Insights Network	RCV000008145	SCV001749975	not provided	PMM2-congenital disorder of glycosylation		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 02-19-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000078590	SCV001800330	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000078590	SCV001925184	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078590	SCV001957730	pathogenic	not provided		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000008145	SCV002070493	pathogenic	PMM2-congenital disorder of glycosylation	2021-06-21	no assertion criteria provided	clinical testing	DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.422G>A, in exon 5 that results in an amino acid change, p.Arg141His. The p.Arg141His sequence change has been observed in 0.4% of individuals in the gnomAD database, in the heterozygous state, and is regarded as the most common pathogenic variant found in patients with PMM2-related congenital disorders of glycosylation (PMID: 20301289). The p.Arg141His change affects a highly conserved amino acid residue located in a domain of the PMM2 protein that is known to be functional. The p.Arg141His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in an estimated 40% of individuals with PMM2-related congenital disorders of glycosylation (CDG), in the compound heterozygous state with a second variant (PMID: 20301289, 21541725). Functional studies have also demonstrated that the p.Arg141His change reduces protein stability and enzymatic activity in vitro (PMID: 26014514)
GenomeConnect, ClinGen	RCV000008145	SCV002818370	not provided	PMM2-congenital disorder of glycosylation		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 06-29-2018 by Lab or GTR ID 1238. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.