ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.200T>G (p.Val67Gly)

gnomAD frequency: 0.00003  dbSNP: rs751986971
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000367998 SCV000338360 uncertain significance not provided 2015-12-14 criteria provided, single submitter clinical testing
Counsyl RCV000670646 SCV000795526 uncertain significance PMM2-congenital disorder of glycosylation 2017-11-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000670646 SCV002241044 pathogenic PMM2-congenital disorder of glycosylation 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 67 of the PMM2 protein (p.Val67Gly). This variant is present in population databases (rs751986971, gnomAD 0.004%). This missense change has been observed in individual(s) with congenital disorder of gylcosylation type Ia (PMID: 16435227). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 285370). 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%. This variant disrupts the p.Val67 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been observed in individuals with PMM2-related conditions (PMID: 11058896), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155149 SCV003845005 uncertain significance not specified 2023-02-20 criteria provided, single submitter clinical testing Variant summary: PMM2 c.200T>G (p.Val67Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251388 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.200T>G has been reported in the literature in at least one individual affected with Congenital Disorder Of Glycosylation Type 1a. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic n=1, VUS n=2). In addition, p.V67M has also been reported to associate with Congenital Disorder Of Glycosylation Type 1a. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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