ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.422G>A (p.Arg141His) (rs28936415)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078590 SCV000230903 pathogenic not provided 2015-11-11 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000008145 SCV000236521 pathogenic Congenital disorder of glycosylation, type Ia 2015-02-18 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000008145 SCV000248535 pathogenic Congenital disorder of glycosylation, type Ia 2015-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000078590 SCV000321929 pathogenic not provided 2018-10-28 criteria provided, single submitter clinical testing The R141H variant in the PMM2 gene has been reported previously in the compound heterozygous state in multiple unrelated individuals with CDG-1a (Matthijs et al., 1997; Kjaergaard et al., 2001; Vega et al., 2011). This variant is 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). The R141H variant is observed in 172/20,902 alleles (0.82%) from individuals of Finnish background, and 860/217,396 global alleles (0.4%) with no homozygous control individuals reported, in large population cohorts (Lek et al., 2016). While the R141H variant is a conservative amino acid substitution, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies of the R141H mutant enzyme in bacteria demonstrated reduced enzyme stability and catalytic activity below detection limits (Vega et al., 2011). Therefore, we interpret R141H to be a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000008145 SCV000399674 pathogenic Congenital disorder of glycosylation, type Ia 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 Congenital disorder of glycosylation, type Ia 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000008145 SCV000633725 pathogenic Congenital disorder of glycosylation, type Ia 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 141 of the PMM2 protein (p.Arg141His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs28936415, ExAC 2.8%). This variant is the most common cause of PMM2-CDG in European populations (PMID: 9497260, 11517108, 21541725, 25355454, 19357119). It has been reported as compound heterozygous in multiple affected individuals and patient fibroblasts carrying this variant show residual PPM2 activities of 16-31% (PMID: 21541725). ClinVar contains an entry for this variant (Variation ID: 7706). Experimental studies have shown that this missense change reduces protein stability and enzymatic activity in vitro (PMID: 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000008145 SCV000678089 pathogenic Congenital disorder of glycosylation, type Ia 2015-06-06 criteria provided, single submitter clinical testing
Centre for Arab Genomic Studies,Sheikh Hamdan Award for Medical Sciences RCV000008145 SCV000693883 pathogenic Congenital disorder of glycosylation, type Ia 2017-07-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000008145 SCV000696497 pathogenic Congenital disorder of glycosylation, type Ia 2016-02-12 criteria provided, single submitter clinical testing Variant summary: c.422G>A affects a conserved nucleotide, resulting in amino acid change from Arg to His. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 213/32256 control chromosomes at a frequency of 0.0066034, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0055902). This variant has been reported in multiple CDG pts and functional studies showed that this variant severely affected the proteins stability as well as catalytic activity (Vega_2011 and Yuste-Checa_2015). In addition, multiple clinical laboratories/reputable database classified this variant as pathogenic. Taken together, this variant was classified as a Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000008145 SCV000711768 pathogenic Congenital disorder of glycosylation, type Ia 2018-12-04 criteria provided, single submitter clinical testing The p.Arg141His variant in PMM2 has been reported in several compound heterozygo us individuals with congenital disorder of glycosylation type Ia and is one of t he most frequent pathogenic variants in patients with this disorder (Matthijs 19 97, Matthijs 1998, de Lonlay 2001). This variant has also been reported in ClinV ar (Variation ID#7706), as pathogenic by multiple laboratories. Functional stud ies provide evidence that this variant causes complete loss of enzyme activity ( Vega 2011, Andreotti 2015). The p.Arg141His variant has never been observed in h omozygosity, suggesting that the total absence of PMM2 activity is not compatibl e with life (Matthijs 1998). This variant has been identified in 0.8% (172/20902 ) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency . In summary, this variant meets our criteria to be classified as pathogenic for congenital disorder of glycosylation type Ia in an autosomal recessive manner b ased upon its co-occurrence with other pathogenic variants in patients and funct ional evidence. ACMG/AMP Criteria applied: PM3_Very Strong, PS3.
Ambry Genetics RCV000624874 SCV000741460 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000008145 SCV000743895 pathogenic Congenital disorder of glycosylation, type Ia 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000008145 SCV000745326 pathogenic Congenital disorder of glycosylation, type Ia 2017-09-14 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000008145 SCV000809108 pathogenic Congenital disorder of glycosylation, type Ia 2018-06-18 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000008145 SCV000996184 pathogenic Congenital disorder of glycosylation, type Ia 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.
OMIM RCV000008145 SCV000028350 pathogenic Congenital disorder of glycosylation, type Ia 2007-05-01 no assertion criteria provided literature only
GeneReviews RCV000008145 SCV000040585 pathologic Congenital disorder of glycosylation, type Ia 2011-04-21 no assertion criteria provided curation Converted during submission to Pathogenic.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000008145 SCV000733550 pathogenic Congenital disorder of glycosylation, type Ia no assertion criteria provided clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000008145 SCV000745882 pathogenic Congenital disorder of glycosylation, type Ia 2017-02-12 no assertion criteria provided clinical testing
Dobyns Lab,Seattle Children's Research Institute RCV000008145 SCV000916324 pathogenic Congenital disorder of glycosylation, type Ia 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

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