ClinVar Miner

Submissions for variant NM_001077365.2(POMT1):c.1939G>A (p.Ala647Thr) (rs119462987)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000414180 SCV000336993 pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing
GeneDx RCV000414180 SCV000491141 pathogenic not provided 2018-02-22 criteria provided, single submitter clinical testing The A669T variant in the POMT1 gene has been reported previously in association with POMT1-related disorders, in affected individuals who were heterozygous for the A669T variant and another variant (D'Amico et al., 2006; Godfrey et al., 2007; Manya et al., 2008; Wallace et al., 2014). The A669T variant is not observed in large population cohorts (Lek et al., 2016). The A669T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret A669T as a pathogenic variant.
Invitae RCV000694423 SCV000822869 pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C1; Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B1; Walker-Warburg congenital muscular dystrophy 2019-02-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 669 of the POMT1 protein (p.Ala669Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in combination with another POMT1 variant in individuals affected with congenital muscular dystrophy and limb girdle muscular dystrophy (PMID: 16717220, 17878207, 20816175, 17869517, Invitae). Cardiomyopathy was subsequently reported to have developed in one of these individuals (PMID: 22549409). 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: 3250). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000414180 SCV000843357 likely pathogenic not provided 2017-09-14 criteria provided, single submitter clinical testing
OMIM RCV000003406 SCV000023564 pathogenic MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 1 2012-12-01 no assertion criteria provided literature only

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