Submissions for variant NM_000257.4(MYH7):c.2347C>T (p.Arg783Cys)

dbSNP: rs727503258

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158529	SCV000208464	likely pathogenic	not provided	2023-06-10	criteria provided, single submitter	clinical testing	Reported in association with HCM in published literature; however, detailed clinical information was not provided (Homburger et al., 2016; Bonaventure et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 34135346, 27532257, 29300372, 27247418, 31110529, 30275503)
Color Diagnostics, LLC DBA Color Health	RCV001180078	SCV001344932	uncertain significance	Cardiomyopathy	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 783 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 31110529). Different variants affecting the same codon, p.Arg783His and p.Arg783Pro, are considered to be disease-causing (ClinVar variation ID: 180437 and 42895), suggesting that arginine at this position is important for MYH7 protein function. This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002426777	SCV002731891	uncertain significance	Cardiovascular phenotype	2024-06-04	criteria provided, single submitter	clinical testing	The p.R783C variant (also known as c.2347C>T), located in coding exon 19 of the MYH7 gene, results from a C to T substitution at nucleotide position 2347. The arginine at codon 783 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been reported in hypertrophic cardiomyopathy (HCM) cohorts (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 Jun;113:6701-6; Robert-Paganin J et al. Nat Commun, 2018 Oct;9:4019; Bonaventura J et al. Arch Med Sci, 2019 May;15:641-649; Bonaventura J et al. J Am Heart Assoc, 2024 May;13:e033565). Another variant at the same codon, p.R783H (c.2348G>A), has been detected in numerous individual from hypertrophic cardiomyopathy (HCM) cohorts and cohorts referred for HCM genetic testing (Waldm&uuml;ller S et al. Clin. Chem., 2008 Apr;54:682-7; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Lopes LR et al. Heart, 2015 Feb;101:294-301; J&auml;&auml;skel&auml;inen P et al. ESC Heart Fail. 2019 Apr;6(2):436-445; Marschall C et al. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298; Hathaway J et al. BMC Cardiovasc Disord. 2021 03;21(1):126; Phan PD et al. JRSM Cardiovasc Dis. 2024 Jan;13:20480040231220100; Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Revvity Omics, Revvity	RCV000158529	SCV003817675	uncertain significance	not provided	2021-08-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003748196	SCV004558277	likely pathogenic	Hypertrophic cardiomyopathy	2024-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 783 of the MYH7 protein (p.Arg783Cys). This variant is present in population databases (rs727503258, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 181182). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg783 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21211974). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV001180078	SCV004820365	uncertain significance	Cardiomyopathy	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 783 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 31110529). Different variants affecting the same codon, p.Arg783His and p.Arg783Pro, are considered to be disease-causing (ClinVar variation ID: 180437 and 42895), suggesting that arginine at this position is important for MYH7 protein function. This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003748196	SCV004847822	likely pathogenic	Hypertrophic cardiomyopathy	2019-10-14	criteria provided, single submitter	clinical testing	The p.Arg783Cys variant in MYH7 has been identified in 1 individual with HCM (Homburger 2016). It has been identified in 1/113752 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and in ClinVar (Variation ID: 181182). Computational prediction tools and conservation analysis suggest that the p.Arg783His variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Of note, this variant 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 (Walsh 2016). In addition, 2 other variants involving this codon, p.Arg783His and p.Arg783Pro, have been identified in individuals with cardiomyopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PM5, PP3.
CeGaT Center for Human Genetics Tuebingen	RCV000158529	SCV005330412	likely pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	MYH7: PM1, PM2, PM5