Submissions for variant NM_000303.3(PMM2):c.415G>A (p.Glu139Lys)

dbSNP: rs80338703

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000479820	SCV000230904	pathogenic	not provided	2014-05-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000479820	SCV000568192	pathogenic	not provided	2017-02-07	criteria provided, single submitter	clinical testing	The E139K variant in the PMM2 gene has been reported previously numerous times in association with CDG type 1a (Vullamier-Barrot et al., 1999; Le Bizec et al., 2005; Romano et al., 2009). Functional studies demonstrate that this variant disrupts a splicing enhancer sequence, which causes skipping of exon 5 and ultimately results in decreased protein activity (Vullamier-Barrot et al., 1999; Le Bizec et al., 2005; Smith et al., 2006). The E139K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Missense variants in nearby residues (R141C, R141H, F144L) have been reported in the Human Gene Mutation Database in association with CDG type 1a (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret E139K as a pathogenic variant.
Counsyl	RCV000020235	SCV000791858	likely pathogenic	PMM2-congenital disorder of glycosylation	2017-05-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020235	SCV000918030	pathogenic	PMM2-congenital disorder of glycosylation	2018-11-30	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.415G>A (p.Glu139Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in exon 5 skipping (Vuillaumier-Barrot_1999). The variant was absent in 189894 control chromosomes (gnomAD). The variant, c.415G>A, has been reported in the literature in multiple individuals affected with Congenital Disorder of Glycosylation Type 1a and was reported to be a founder mutation in the French population (Vuillaumier-Barrot_1999, LeBizec_2005). These data indicate that the variant is very likely to be associated with disease. Two publications from the same group report experimental evidence evaluating an impact on protein function (Vuillaumier-Barrot_1999, LeBizec_2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion	RCV000020235	SCV002011979	pathogenic	PMM2-congenital disorder of glycosylation	2021-10-02	criteria provided, single submitter	clinical testing	The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (VCV000021143.5, PMID: 15844218, 19357119, PM3_S). It is not observed in the gnomAD v2.1.1 dataset (PM2). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 15844218). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.701, 3Cnet: 0.940, PP3). Patient's phenotype is considered compatible with Congenital disorder of glycosylation, type Ia (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV000020235	SCV003443499	pathogenic	PMM2-congenital disorder of glycosylation	2023-09-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 10571956). Experimental studies have shown that this missense change affects PMM2 function (PMID: 10571956). 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. ClinVar contains an entry for this variant (Variation ID: 21143). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1a (PMID: 10571956). 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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 139 of the PMM2 protein (p.Glu139Lys).
GeneReviews	RCV000020235	SCV000040584	not provided	PMM2-congenital disorder of glycosylation		no assertion provided	literature only
Dobyns Lab, Seattle Children's Research Institute	RCV000020235	SCV000916323	pathogenic	PMM2-congenital disorder of glycosylation	2019-02-18	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001257997	SCV001434810	likely pathogenic	Congenital cerebellar hypoplasia		no assertion criteria provided	research
Natera, Inc.	RCV000020235	SCV002089481	pathogenic	PMM2-congenital disorder of glycosylation	2021-03-09	no assertion criteria provided	clinical testing