Submissions for variant NM_000303.3(PMM2):c.563A>G (p.Asp188Gly)

gnomAD frequency: 0.00001  dbSNP: rs80338704

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790726	SCV000232043	pathogenic	not provided	2016-09-29	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000008151	SCV000743897	pathogenic	PMM2-congenital disorder of glycosylation	2017-07-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000008151	SCV000799182	likely pathogenic	PMM2-congenital disorder of glycosylation	2018-04-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000008151	SCV001201500	pathogenic	PMM2-congenital disorder of glycosylation	2022-12-22	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 7712). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PMM2 function (PMID: 10386614). 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. This missense change has been observed in individual(s) with PMM2-related conditions (PMID: 9497260, 24139637). This variant is present in population databases (rs80338704, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 188 of the PMM2 protein (p.Asp188Gly).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000008151	SCV001983449	pathogenic	PMM2-congenital disorder of glycosylation	2021-09-29	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.563A>G (p.Asp188Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251478 control chromosomes. c.563A>G has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, Matthijs_1998, de la Morena-Barrio_2013, Starosta_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000008151	SCV000028356	pathogenic	PMM2-congenital disorder of glycosylation	1998-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000008151	SCV000040586	not provided	PMM2-congenital disorder of glycosylation		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000008151	SCV000733552	pathogenic	PMM2-congenital disorder of glycosylation		no assertion criteria provided	clinical testing