Submissions for variant NM_000303.3(PMM2):c.43G>A (p.Gly15Arg)

gnomAD frequency: 0.00001  dbSNP: rs767831048

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000673598	SCV001203290	pathogenic	PMM2-congenital disorder of glycosylation	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 15 of the PMM2 protein (p.Gly15Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1a (PMID: 28454995; 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: 557455). 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 determined to be pathogenic (PMID: 12626389; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001536229	SCV001752956	pathogenic	not provided	2023-09-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15520415, 28454995, 33101984)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000673598	SCV003922623	pathogenic	PMM2-congenital disorder of glycosylation	2023-03-06	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.43G>A (p.Gly15Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-06 in 237144 control chromosomes (gnomAD). c.43G>A has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation (example: Schollen_2004, Alfares_2017, and Silver_2021). Different nucleotide changes affecting the same amino acid (c.44G>C p.G15A, c.43G>C p.G15R, c.44G>A p.G15E) is associated with Congenital disorder of glycosylation 1a in HGMD. This suggests that this residue is critical for the normal protein function. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1), pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000673598	SCV004024518	pathogenic	PMM2-congenital disorder of glycosylation	2023-07-20	criteria provided, single submitter	clinical testing	This PMM2 variant (rs767831048) is rare (<0.1%) in a large population dataset (gnomAD: 3/268534 total alleles; 0.0011%; no homozygotes) and has been reported in ClinVar. This variant has been observed in individuals with PMM2-CMG; different nucleotide changes affecting the same amino acid have also been reported. Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the other predicts that it would be tolerated. The glycine residue at this position is strongly conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 1 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.43G>A (p.Gly15Arg) to be pathogenic for PMM2-CDG.
Baylor Genetics	RCV000673598	SCV004205291	likely pathogenic	PMM2-congenital disorder of glycosylation	2024-03-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000673598	SCV000798821	uncertain significance	PMM2-congenital disorder of glycosylation	2018-03-26	flagged submission	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000673598	SCV001133221	likely pathogenic	PMM2-congenital disorder of glycosylation	2019-09-26	no assertion criteria provided	clinical testing