ClinVar

Description

Variant summary: MYH7 c.4402G>A (p.Glu1468Lys) results in a conservative amino acid change located in the myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251430 control chromosomes (gnomAD). c.4402G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Mattos_2016, Bottillo_2016, Homburger_2016, Miller_2019) and has been reported to segregate with the disease phenotype within affected families, although multiple unaffected family members were also reported with the variant, suggesting a reduced penetrance (Mattos_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26656175, 30297972, 27247418, 27737317, 31199839). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Three submitters classified the variant as pathogenic/likely pathogenic and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.