ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.3346C>A (p.Arg1116Ser) (rs372446459)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172029 SCV000050990 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000172029 SCV000576525 uncertain significance not provided 2017-04-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH6 gene. The R1116S variant has been reported in association with HCM and congenital heart defects (Lopes et al., 2015; Granados-Riveron et al., 2010); however, additional clinical details and segregation information were not provided. Furthermore, this variant was reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013). Nevertheless, the R1116S 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 R1116S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000545287 SCV000648244 uncertain significance Familial hypertrophic cardiomyopathy 14 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 1116 of the MYH6 protein (p.Arg1116Ser). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs372446459, ExAC 0.01%). This variant has been reported in the literature in one individual affected with atrial septal defects (ASD) (PMID: 20656787) and in one individual affected with dilated cardiomyopathy (DCM) (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 191717). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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