ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.385G>A (p.Val129Met) (rs104894525)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000008147 SCV000220186 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2014-03-23 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000344673 SCV000331816 pathogenic not provided 2018-04-24 criteria provided, single submitter clinical testing
GeneDx RCV000344673 SCV000329702 pathogenic not provided 2016-08-18 criteria provided, single submitter clinical testing The V129M pathogenic variant in the PMM2 gene has been reported previously in a compound heterozygous state with other pathogenic PMM2 variants in individuals with clinical and/or biochemical evidence of CDG-1a (Matthijs et al., 1997; Barone et al., 2008). The V129M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In vitro studies in E. coli have shown that this variant leads to a decrease in the activity and stability of the phosphomannomutase enzyme (Pirard et al., 1999). We interpret V129M as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000008147 SCV000696496 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-02-23 criteria provided, single submitter clinical testing Variant summary: The PMM2 c.385G>A (p.Val129Met) variant located in the HAD-like domain (via InterPro) involves the alteration of a conserved nucleotide, which 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/31420, which does not exceed the estimated maximal expected allele frequency for a pathogenic PMM2 variant of 1/178. Multiple publications have cited the variant in affected individuals presenting with both severe and mild phenotypes dependent upon the PMM2 variant in trans. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
OMIM RCV000008147 SCV000028352 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 1997-05-01 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000008147 SCV000803499 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Congenital disorder of glycosylation, type Ia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:11058896). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:10386614).

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