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	likely pathogenic	PMM2-congenital disorder of glycosylation	2019-12-19	criteria provided, single submitter	clinical testing	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. 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: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of PMM2-congenital disorder of glycosylation (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 553249). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 15 of the PMM2 protein (p.Gly15Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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