Submissions for variant NM_000303.3(PMM2):c.669C>A (p.Asp223Glu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV003463305	SCV004205306	likely pathogenic	PMM2-congenital disorder of glycosylation	2023-02-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003463305	SCV004296391	pathogenic	PMM2-congenital disorder of glycosylation	2023-04-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp223 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been observed in individuals with PMM2-related conditions (PMID: 12357336), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects PMM2 function (PMID: 10602363). 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 clinical features of autosomal recessive PMM2-congenital disorder of glycosylation (PMID: 9781039, 10602363, 11058896, 26887550). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 223 of the PMM2 protein (p.Asp223Glu).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003463305	SCV005039236	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-03-22	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.669C>A (p.Asp223Glu) results in a 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 was absent in 251278 control chromosomes. c.669C>A has been reported in the literature in three individuals affected with autosomal recessive Congenital Disorder Of Glycosylation (example, AbuBakar_2022, Kjaergaard_1998, Ren_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35279850, 10602363, 26887550). ClinVar contains an entry for this variant (Variation ID: 2677894). Based on the evidence outlined above, the variant was classified as likely pathogenic.