ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000008147 SCV000220186 likely pathogenic Congenital disorder of glycosylation, type Ia 2014-03-23 criteria provided, single submitter literature only
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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000344673 SCV000331816 pathogenic not provided 2018-04-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000008147 SCV000696496 pathogenic Congenital disorder of glycosylation, type Ia 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.
SIB Swiss Institute of Bioinformatics RCV000008147 SCV000803499 likely pathogenic Congenital disorder of glycosylation, type Ia 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).
Invitae RCV000008147 SCV001215077 pathogenic Congenital disorder of glycosylation, type Ia 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 129 of the PMM2 protein (p.Val129Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs104894525, ExAC 0.01%). This variant has been observed in individual(s) with congenital disorder of glycosylation type 1a (CDG1a) (PMID: 18629883, 18948042, 9140401). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7708). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000008147 SCV000028352 pathogenic Congenital disorder of glycosylation, type Ia 1997-05-01 no assertion criteria provided literature only
Pediatric Metabolic Diseases,Hacettepe University RCV000008147 SCV000998571 likely pathogenic Congenital disorder of glycosylation, type Ia no assertion criteria provided clinical testing

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