ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3134G>T (p.Arg1045Leu) (rs397516178)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035841 SCV000059492 uncertain significance not specified 2016-06-22 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1045Le u variant in MYH7 has been observed in 2 individuals with HCM and segregated wit h disease in 2 affected relatives by our laboratory. This variant has also been identified in 2/66738 of European chromosomes by the Exome Aggregation Consortiu m (ExAC,; dbSNP rs397516178). This variant was pr edicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogen ic role, the clinical significance of the p.Arg1045Leu variant is uncertain.
GeneDx RCV000035841 SCV000208523 uncertain significance not specified 2017-03-16 criteria provided, single submitter clinical testing The R1045L variant in the MYH7 gene has been reported in one individual with HCM and segregated with disease in one relative (Cann et al., 2016). The R1045L 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 R1045L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. 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. Lastly, other amino acid substitutions at this residue (R1045C, R1045H) and in nearby residues (V1044A, R1050Q) have been reported in association with HCM (Stenson et al., 2014), though the precise clinical significance of these variants currently remains unclear.
Invitae RCV000629019 SCV000749929 pathogenic Hypertrophic cardiomyopathy 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 1045 of the MYH7 protein (p.Arg1045Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs397516178, ExAC 0.003%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42948). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. Different missense substitutions at this codon (p.Arg1045His, p.Arg1045Cys) have been reported in individuals affected with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 27532257, 18533079, 20215591, 27247418, 26914223, 24793961). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845446 SCV000987531 likely pathogenic Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing

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