ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.131T>C (p.Val44Ala)

dbSNP: rs104894534
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000008164 SCV000486888 likely pathogenic PMM2-congenital disorder of glycosylation 2016-08-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000008164 SCV001372414 pathogenic PMM2-congenital disorder of glycosylation 2020-06-04 criteria provided, single submitter clinical testing Variant summary: PMM2 c.131T>C (p.Val44Ala) results in a non-conservative amino acid change located in the Phosphomannomutase domain (IPR005002) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249792 control chromosomes. c.131T>C has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, Matthijs_1998, Grunwald_2001, Vega_2011, Izquierdo-Serra_2018). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity and characterization as a misfolding defect resulting in protein destabilization (example, Vega_2011, Yuste-Checa_2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000008164 SCV002233246 pathogenic PMM2-congenital disorder of glycosylation 2021-08-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725, 26014514). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 7725). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1 (PMID: 9497260, 21541725). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 44 of the PMM2 protein (p.Val44Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine.
Baylor Genetics RCV000008164 SCV004205280 pathogenic PMM2-congenital disorder of glycosylation 2023-05-31 criteria provided, single submitter clinical testing
OMIM RCV000008164 SCV000028369 pathogenic PMM2-congenital disorder of glycosylation 2007-04-01 no assertion criteria provided literature only
Natera, Inc. RCV000008164 SCV002089468 pathogenic PMM2-congenital disorder of glycosylation 2020-03-22 no assertion criteria provided clinical testing

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