ClinVar Miner

Submissions for variant NM_000257.3(MYH7):c.1826A>G (p.Tyr609Cys) (rs727504925)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000557354 SCV000623652 likely pathogenic Hypertrophic cardiomyopathy 2017-04-17 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 609 of the MYH7 protein (p.Tyr609Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (rs727504925, ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21750094, 27247418, Invitae). ClinVar contains an entry for this variant where it was observed in an additional individual with hypertrophic cardiomyopathy (Variation ID: 179525). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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. In summary, this variant is a rare missense variant that has been observed in several affected individuals, is predicted to be deleterious, and is found in a clinically important region of MYH7. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156316 SCV000206034 uncertain significance not specified 2014-02-11 criteria provided, single submitter clinical testing The Tyr609Cys variant in MYH7 has been previously reported in one individual with HCM (Waldmüller 2011), and has now been identified by our laboratory in one individual with HCM and segregated with HCM in one affected relative. This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of this variant.

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