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

gnomAD frequency: 0.00003  dbSNP: rs751986971

Total submissions: 4

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
Invitae	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.