Submissions for variant NM_000303.3(PMM2):c.44G>C (p.Gly15Ala)

dbSNP: rs958073558

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668655	SCV001214942	pathogenic	PMM2-congenital disorder of glycosylation	2024-05-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 15 of the PMM2 protein (p.Gly15Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PMM2-congenital disorder of glycosylation (PMID: 33413482; Invitae). 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: 553249). 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.Gly15 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been observed in individuals with PMM2-related conditions (PMID: 12626389, 28454995; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000668655	SCV001435297	pathogenic	PMM2-congenital disorder of glycosylation	2020-04-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000668655	SCV005056368	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-02-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668655	SCV005381496	pathogenic	PMM2-congenital disorder of glycosylation	2024-08-30	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.44G>C (p.Gly15Ala) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.44G>C has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a (example:Baker_2019, Starosta_2021, Stranneheim_2021) . These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.43G>A, p.Gly15Arg), supporting the critical relevance of codon 15 to PMM2 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 33413482, 30577886, 33726816). ClinVar contains an entry for this variant (Variation ID: 553249). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl	RCV000668655	SCV000793289	uncertain significance	PMM2-congenital disorder of glycosylation	2017-08-08	flagged submission	clinical testing