Submissions for variant NM_000257.4(MYH7):c.5134C>T (p.Arg1712Trp)

dbSNP: rs121913650

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000546277	SCV001842664	likely pathogenic	Hypertrophic cardiomyopathy	2021-06-16	reviewed by expert panel	curation	The c.5134C>T (p.Arg1712Trp) variant in MYH7 has been reported in the heterozygous state in at least 13 individuals with HCM, 2 of whom also had additional variants in other HCM-associated genes (PS4_Moderate; Hougs 2005 PMID:15483641; Gruner 2011 PMID:21511876; Jensen 2013 PMID:23197161; Hagen 2013 PMID:24498601; Mu 2019 https://www.actamedicamediterranea.com/archive/2019/medica-5/pathogenic-mutation-detection-and-correlation-analysis-between-genotype-and-phenotype-of-familial-hypertrophic-cardiomyopathy-in-chinese-han-nationality/pdf; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with HCM in at least 6 affected relatives from 4 families (PP1_Moderate; Hougs 2005 PMID:15483641; Mu 2019; Ambry pers comm.; Centenary Institute Sydney pers comm.). This variant has also been identified in the homozygous state in 2 siblings from a consanguineous family with myopathy and normal cardiac function (Beecroft 2019 PMID:31130376). Data from the gnomAD population database (v2.1.1) is insufficient to assess the frequency of this variant; however, this variant is absent from the ExAC database (PM2; http://gnomad.broadinstitute.org; http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Moderate; PP1_Moderate; PM2; PP3.
GeneDx	RCV000480992	SCV000565293	likely pathogenic	not provided	2023-09-27	criteria provided, single submitter	clinical testing	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; In silico analysis also suggests this variant may impact gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 24498601, 23197161, 19035361, 25961035, 15483641, 32710294, 34691145, 36264615, 36243179, 32894683, 21511876, Mu_2019_article, 31130376)
Invitae	RCV000546277	SCV000623734	pathogenic	Hypertrophic cardiomyopathy	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1712 of the MYH7 protein (p.Arg1712Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15483641; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14118). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg1712 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18403758, 21511876, 23785128, 24510615, 27247418, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000546277	SCV000710842	likely pathogenic	Hypertrophic cardiomyopathy	2020-07-14	criteria provided, single submitter	clinical testing	The p.Arg1712Trp variant in MYH7 has been reported in the heterozygous state in at least 6 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 6 affected individuals from two families (Hougs 2005 PMID:15483641, Gruner 2011 PMID:21511876, Jensen 2013 PMID:23197161, Hagen 2013 PMID:24498601, Mu 2019, LMM data). One of these individuals also carried another disease-causing variant in another HCM gene (Gruner 2011 PMID:21511876). This variant has also been identified in the homozygous state in 2 siblings from a consanguineous family with myopathy and normal cardiac function (Beecroft 2019 PMID:31130376). This variant been reported by other clinical laboratories in ClinVar (Variation ID 14118). Data from the gnomAD population database is insufficient to assess the frequency of this variant; however, this variant is absent from the ExAC database (http://gnomad.broadinstitute.org; http://exac.broadinstitute.org). In vitro functional studies provide some evidence that this variant impacts protein function (Beecroft 2019 PMID:31130376) and computational prediction tools and conservation analysis are consistent with pathogenicity. An additional variant involving this codon (p.Arg1712Gln) has been identified in individuals with HCM and is classified as likely pathogenic by the ClinGen Inherited Cardiomyopathy Expert Panel (SCV000564455.2). 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: PS4_Supporting, PP1_Moderate, PM2, PS3_Supporting, PP3, PM5_Supporting.
Ambry Genetics	RCV002345244	SCV002646610	likely pathogenic	Cardiovascular phenotype	2023-01-05	criteria provided, single submitter	clinical testing	The p.R1712W variant (also known as c.5134C>T), located in coding exon 33 of the MYH7 gene, results from a C to T substitution at nucleotide position 5134. The arginine at codon 1712 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected in several hypertrophic cardiomyopathy (HCM) cohorts and individuals reported to have HCM (Hougs L et al. Eur. J. Hum. Genet. 2005;13:161-5; Glotov AS et al. Clin. Chim. Acta. 2015;446:132-40; Burns C et al. Circ Cardiovasc Genet. 2017;10:e001666; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; Ambry internal data). In one family, both this alteration and an alteration in MT-CYB (p.C93Y) were observed to segregate with disease (Hagen CM et al. Mol Genet Genomic Med. 2013;1:54-65). This alteration has also been reported in the homozygous state in siblings with myopathy (Beecroft SJ et al. Neuromuscul. Disord., 2019 Jun;29:456-467). Another variant impacting this codon (p.R1712Q) has also been reported in association with HCM (Morita H et al. N. Engl. J. Med. 2008;358:1899-908). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	RCV003319168	SCV003932411	pathogenic	Primary familial hypertrophic cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532358	SCV004716659	likely pathogenic	MYH7-related disorder	2023-11-08	criteria provided, single submitter	clinical testing	The MYH7 c.5134C>T variant is predicted to result in the amino acid substitution p.Arg1712Trp. This variant was reported to segregate in families and other unrelated individuals with hypertrophic cardiomyopathy (Hougs et al. 2005. PubMed ID: 15483641; Supp. Table 1 in Ho et al. 2018. PubMed ID: 30297972; Hagen et al. 2013. PubMed ID: 24498601; Supp. Table 2 in Burns et al. 2017. PubMed ID: 28790153). This variant was also reported in the homozygous state in two siblings with features of a congenital myopathy (Beecroft et al. 2019. PubMed ID: 31130376). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has also been reported as likely pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/14118/). This variant is interpreted as likely pathogenic.
All of Us Research Program, National Institutes of Health	RCV000546277	SCV004834024	likely pathogenic	Hypertrophic cardiomyopathy	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1712 in the LMM domain of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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: 15483641, 23197161, 24498601, 25892673, 28790153, 30297972, doi:10.19193/0393-6384_2019_5_383). Some of these individuals also carried a mitochondrial variant in the MT-CYB gene (PMID: 24498601). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 24498601, doi:10.19193/0393-6384_2019_5_383). This variant has also been reported in homozygous state in two siblings affected with recessive myopathy with no cardiac involvement; both heterozygous parents were unaffected (PMID: 31130376). A different variant occurring at the same codon, p.Arg1712Gln, is a well documented pathogenic mutation (Clinvar variation ID: 36642), indicating that arginine at this position is important for MYH7 protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
OMIM	RCV000015175	SCV000035432	pathogenic	Hypertrophic cardiomyopathy 1	2005-02-01	no assertion criteria provided	literature only
OMIM	RCV003151728	SCV003841183	pathogenic	Myopathy, myosin storage, autosomal recessive	2005-02-01	no assertion criteria provided	literature only