ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5380C>A (p.Gln1794Lys) (rs397516247)

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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 RCV000035961 SCV000059613 likely pathogenic Hypertrophic cardiomyopathy 2018-11-23 criteria provided, single submitter clinical testing The p.Gln1794Lys variant in MYH7 has been identified in 5 individuals with HCM ( Xu 2015, Walsh 2017, GeneDx pers. comm., LMM data) and was found to have occurre d apparently de novo in one individual with childhood onset HCM (GeneDx pers. co mm.). It was absent from large population studies but has been reported in ClinV ar (Variation ID # 43066). The p.Gln1794Glu variant in MYH7 has also been identi fied in individuals with HCM, however, the clinical significance of this variant is currently uncertain. Glutamine (Gln) at position 1794 is highly conserved in mammals and across evolutionarily distant species and the change to lysine (Lys ) was predicted to be pathogenic using a computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well-established clinical significance. This tool's pathogenic prediction is estimated to be corr ect 94% of the time (Jordan 2011). In summary, although additional studies are r equired to fully establish its clinical significance, this variant meets criteri a to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Cri teria applied: PS4_Moderate, PP3, PM2, PM6.
GeneDx RCV000488979 SCV000577699 likely pathogenic not provided 2018-05-10 criteria provided, single submitter clinical testing The Q1794K variant in the MYH7 gene has reported previously in association with HCM (Xu et al., 2015; Walsh et al., 2017), although specific clinical details were not provided. In addition, Q1794K has been identified as an assumed de novo occurrence in one individual, and observed independently of additional cardiogenetic variants in another individual referred for cardiomyopathy genetic testing at GeneDx. The Q1794K variant is not observed in large population cohorts (Lek et al., 2016). The Q1794K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Thus, Q1794K in the MYH7 gene is interpreted as a likely pathogenic variant.

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