ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.458T>C (p.Ile153Thr) (rs150577656)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409634 SCV000486977 likely pathogenic Congenital disorder of glycosylation, type Ia 2016-09-14 criteria provided, single submitter clinical testing
Invitae RCV000409634 SCV000960841 pathogenic Congenital disorder of glycosylation, type Ia 2020-08-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 153 of the PMM2 protein (p.Ile153Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs150577656, ExAC 0.002%). This variant has been observed in individual(s) with congenital disorder of glycosylation (PMID: 11156536, 25497157, 26502900, 11058895, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 371406). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). For these reasons, this variant has been classified as Pathogenic. 5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000409634 SCV001363464 pathogenic Congenital disorder of glycosylation, type Ia 2020-11-11 criteria provided, single submitter clinical testing Variant summary: PMM2 c.458T>C (p.Ile153Thr) 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 1.6e-05 in 251354 control chromosomes. c.458T>C has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (e.g. Callewaert_2003, De Lonlay_2001, Lavieu_2005, Serrano_2017, Chan_2016). These data indicate that the variant is very likely to be associated with disease. Compound heterozygote individuals with the variant of interest were found to have PMM activity ranging from 9 to 25% (e.g. Lavieu_2005, Sharma_2011, Chan_2016). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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