ClinVar Miner

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

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
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
Centre for Arab Genomic Studies,Sheikh Hamdan Award for Medical Sciences RCV000008145 SCV000693883 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-07-15 criteria provided, single submitter clinical testing
Counsyl RCV000008145 SCV000678089 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2015-06-06 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000008145 SCV000236521 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2015-02-18 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000008145 SCV000745326 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-09-14 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000008145 SCV000733550 pathogenic Carbohydrate-deficient glycoprotein syndrome type I no assertion criteria provided clinical testing
Dobyns Lab,Seattle Children's Research Institute RCV000008145 SCV000916324 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2019-02-18 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078590 SCV000230903 pathogenic not provided 2015-11-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000008145 SCV000611238 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-05-18 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.
GeneReviews RCV000008145 SCV000040585 pathologic Carbohydrate-deficient glycoprotein syndrome type I 2011-04-21 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000008145 SCV000248535 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2015-06-05 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000008145 SCV000743895 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2014-10-08 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000008145 SCV000745882 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-02-12 no assertion criteria provided clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000008145 SCV000399674 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 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.
Integrated Genetics/Laboratory Corporation of America RCV000008145 SCV000696497 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 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.
Invitae RCV000008145 SCV000633725 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000008145 SCV000711768 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000008145 SCV000809108 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-06-18 criteria provided, single submitter clinical testing
OMIM RCV000008145 SCV000028350 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2007-05-01 no assertion criteria provided literature only

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