ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000629019 SCV000059492 likely pathogenic Hypertrophic cardiomyopathy 2019-12-18 criteria provided, single submitter clinical testing The p.Arg1045Leu variant in MYH7 has been identified in at least 11 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 4 affected relatives from 3 families (Cann 2017, Walsh 2017, Invitae pers. comm., GeneDx pers. comm., LMM data). It has also been identified in 1 individual with HCM who carried an additional pathogenic variant in MYH7 (LMM data). This variant has also reported by other clinical laboratories in ClinVar (Variation ID#42948) and has been identified in 0.004% (4/113744) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg1045Cys) has been identified in individuals with HCM and is classified as likely pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM2, PP1, PP3, PS4_Moderate, PM5_Supporting.
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 2020-10-07 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
Color Health, Inc RCV001188088 SCV001355056 likely pathogenic Cardiomyopathy 2019-10-05 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258092 SCV001434936 likely pathogenic Familial hypertrophic cardiomyopathy 1 2018-10-12 criteria provided, single submitter clinical testing This c.3134G>T (p.Arg1045Leu) variant in the MYH7 gene has been reported in at least three unrelated patients with hypertrophic cardiomyopathy (PMID 25611685, 26914223, 27247418) and is extremely rare in general population databases. A second variant in the same codon, p. Arg1045His was classified likely pathogenic by our laboratory. A third variant at this codon, p.Arg1045Cys was classified as likely pathogenic by expert panel in the Clinvar database, suggesting this arginine residue is critical for MYH7 protein function. Multiple lines of prediction algorithms support the deleterious effect of the c.3134G>T (p.Arg1045Leu) variant. Therefore, this c.3134G>T (p.Arg1045Leu) variant in the MYH7 gene is classified as likely pathogenic.

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