ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2123G>C (p.Gly708Ala) (rs397516134)

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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 RCV000035765 SCV000059416 likely pathogenic Hypertrophic cardiomyopathy 2017-06-06 criteria provided, single submitter clinical testing The p.Gly708Ala variant in MYH7 has been reported in 3 individuals with HCM, 1 i ndividual with LVNC, and segregated with disease in 1 affected relative (Helms 2 014, LMM data). This variant has been reported in ClinVar (Variation ID: 42882). This variant is absent from large population studies. Glycine (Gly) at position 708 is highly conserved in mammals and across evolutionarily distant species an d the change to alanine (Ala) was predicted to be pathogenic using a computation al tool clinically validated by our laboratory. This tool's pathogenic predictio n is estimated to be correct 94% of the time (Jordan 2011). Of note, this varian t lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Wa lsh 2016). In summary, although additional studies are required to fully establi sh its clinical significance, the p.Gly708Ala variant is likely pathogenic.
GeneDx RCV000158509 SCV000208444 likely pathogenic not provided 2015-06-25 criteria provided, single submitter clinical testing p.Gly708Ala (GGC>GCC): c.2123 G>C in exon 19 of the MYH7 gene (NM_000257.2). A G708A variant that is likely pathogenic was identified in the MYH7 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G708A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G708A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, however, it occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, missense mutations in nearby residues (I702V, C705W, P710R, P710H, R712L) have been reported in association with HCM, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in HCM panel(s).

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