ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.415G>A (p.Glu139Lys) (rs80338703)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000020235 SCV000791858 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2017-05-25 criteria provided, single submitter clinical testing
Dobyns Lab,Seattle Children's Research Institute RCV000020235 SCV000916323 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2019-02-18 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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.
GeneReviews RCV000020235 SCV000040584 pathologic Carbohydrate-deficient glycoprotein syndrome type I 2011-04-21 no assertion criteria provided curation Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000020235 SCV000918030 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 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.

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