ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.124G>A (p.Gly42Arg)

gnomAD frequency: 0.00001  dbSNP: rs755402538
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671748 SCV000796764 uncertain significance PMM2-congenital disorder of glycosylation 2017-12-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000671748 SCV001230003 likely pathogenic PMM2-congenital disorder of glycosylation 2023-12-12 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 42 of the PMM2 protein (p.Gly42Arg). This variant is present in population databases (rs755402538, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1a (PMID: 12357336, 15844218). ClinVar contains an entry for this variant (Variation ID: 555844). 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%. 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.
GeneDx RCV001756139 SCV001985340 uncertain significance not provided 2023-09-08 criteria provided, single submitter clinical testing Reported heterozygous in an individual with CDG-1A and intermediated phosphomannomutase activity (Le Bizec et al., 2005); Reported in a patient with CDG-1a who also harbored a second missense variant (Schollen et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 15844218, 34426522, 16009061, 32457805, 35281664, 12357336)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001824863 SCV002074458 uncertain significance not specified 2022-01-28 criteria provided, single submitter clinical testing Variant summary: PMM2 c.124G>A (p.Gly42Arg) 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 variant allele was found at a frequency of 2e-05 in 249876 control chromosomes (gnomAD). c.124G>A has been reported in the literature in compound heterozygous individuals affected with Congenital Disorder Of Glycosylation Type 1a (e.g. Schollen_2002, Tiwary_2022). In addition, Le Bizec et al (2005) describe a heterozygote individual with the variant exhibiting intermediate PMM activity. These data indicate that the variant may be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000671748 SCV002815739 uncertain significance PMM2-congenital disorder of glycosylation 2022-02-16 criteria provided, single submitter clinical testing
Baylor Genetics RCV000671748 SCV004205252 likely pathogenic PMM2-congenital disorder of glycosylation 2024-03-26 criteria provided, single submitter clinical testing
Natera, Inc. RCV000671748 SCV001457165 uncertain significance PMM2-congenital disorder of glycosylation 2020-09-16 no assertion criteria provided clinical testing

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