ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs150577656
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000409634 SCV000960841 pathogenic PMM2-congenital disorder of glycosylation 2023-12-22 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 153 of the PMM2 protein (p.Ile153Thr). This variant is present in population databases (rs150577656, gnomAD 0.002%). This missense change has been observed in individual(s) with congenital disorder of glycosylation (PMID: 11058895, 11156536, 25497157, 26502900; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 371406). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000409634 SCV001363464 pathogenic PMM2-congenital disorder of glycosylation 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.
GeneDx RCV001584105 SCV001819013 pathogenic not provided 2023-08-30 criteria provided, single submitter clinical testing 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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 15844218, 23430838, 30304743, 20506564, 34828263, 33340551, 25525159, 11058895, 11134235, 11156536, 25497157, 28139241, 16085795, 30991241, 28915903, 12626389, 21949237, 12705494, 26502900, 27053713, 31589614, 33413482, 35789514)
Myriad Genetics, Inc. RCV000409634 SCV002060218 likely pathogenic PMM2-congenital disorder of glycosylation 2021-11-16 criteria provided, single submitter clinical testing NM_000303.2(PMM2):c.458T>C(I153T) is a missense variant classified as likely pathogenic in the context of congenital disorder of glycosylation type Ia. I153T has been observed in cases with relevant disease (PMID: 11156536, 11134235, 25497157, 26502900, 15844218, 30991241, 33413482). Functional assessments of this variant are not available in the literature. I153T has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, NM_000303.2(PMM2):c.458T>C(I153T) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics RCV000409634 SCV004205266 pathogenic PMM2-congenital disorder of glycosylation 2023-12-03 criteria provided, single submitter clinical testing

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