Submissions for variant NM_000303.3(PMM2):c.385G>A (p.Val129Met)

dbSNP: rs104894525

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000008147	SCV000220186	likely pathogenic	PMM2-congenital disorder of glycosylation	2014-03-23	criteria provided, single submitter	literature only
GeneDx	RCV000344673	SCV000329702	pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with a decease in the activity and stability of the protein (Pirard et al., 1999); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30577886, 32630370, 25525159, 9140401, 18629883, 31981409, 11409861, 34426522, 33643843, 10386614)
Eurofins Ntd Llc (ga)	RCV000344673	SCV000331816	pathogenic	not provided	2018-04-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000008147	SCV000696496	pathogenic	PMM2-congenital disorder of glycosylation	2017-02-23	criteria provided, single submitter	clinical testing	Variant summary: The PMM2 c.385G>A (p.Val129Met) variant located in the HAD-like domain (via InterPro) involves the alteration of a conserved nucleotide, which 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/31420, which does not exceed the estimated maximal expected allele frequency for a pathogenic PMM2 variant of 1/178. Multiple publications have cited the variant in affected individuals presenting with both severe and mild phenotypes dependent upon the PMM2 variant in trans. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
SIB Swiss Institute of Bioinformatics	RCV000008147	SCV000803499	likely pathogenic	PMM2-congenital disorder of glycosylation	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Congenital disorder of glycosylation, type Ia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:11058896). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:10386614).
Invitae	RCV000008147	SCV001215077	pathogenic	PMM2-congenital disorder of glycosylation	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 129 of the PMM2 protein (p.Val129Met). 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 (CDG1a) (PMID: 9140401, 18629883, 18948042). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7708). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMM2 protein function. This variant disrupts the p.Val129 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16941129). 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.
Fulgent Genetics, Fulgent Genetics	RCV000008147	SCV002775184	pathogenic	PMM2-congenital disorder of glycosylation	2022-01-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000008147	SCV004205299	pathogenic	PMM2-congenital disorder of glycosylation	2023-12-10	criteria provided, single submitter	clinical testing
OMIM	RCV000008147	SCV000028352	pathogenic	PMM2-congenital disorder of glycosylation	1997-05-01	no assertion criteria provided	literature only
Pediatric Metabolic Diseases, Hacettepe University	RCV000008147	SCV000998571	likely pathogenic	PMM2-congenital disorder of glycosylation		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000008147	SCV002089478	pathogenic	PMM2-congenital disorder of glycosylation	2020-10-22	no assertion criteria provided	clinical testing