ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.3758C>T (p.Thr1253Met) (rs201051663)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151216 SCV000199059 uncertain significance not specified 2014-10-22 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Thr1253Met va riant in MHY6 has not been previously reported in individuals with cardiomyopath y or in large population studies. Threonine (Thr) at position 1253 is not conser ved in mammals or in evolutionarily distant species and 2 mammals (macaque and m anatee) have a methionine (Met) at this position, suggesting that this change ma y be tolerated. Additional computational prediction tools suggest that the p.Thr 1253Met variant may impact the protein, though this information is not predictiv e enough to determine pathogenicity. In summary, while the clinical significance of the p.Thr1253Met variant is uncertain, the presence of the variant amino aci d in other mammals suggests that it is more likely to be benign.
GeneDx RCV000766423 SCV000569467 uncertain significance not provided 2017-02-02 criteria provided, single submitter clinical testing The T1253M variant in the MYH6 gene has been reported previously in an individual with sporadic dilated cardiomyopathy (Zhao et al., 2015). The T1253M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1253M 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. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T1253M as a variant of uncertain significance.

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