Submissions for variant NM_000257.4(MYH7):c.610C>T (p.Arg204Cys)

gnomAD frequency: 0.00001  dbSNP: rs397516259

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000628868	SCV002041481	uncertain significance	Hypertrophic cardiomyopathy	2021-04-21	reviewed by expert panel	curation	The NM_000257.4(MYH7):c.610C>T (p.Arg204Cys) variant has been reported in at least 3 individuals with HCM (PS4_Supporting; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.; OMGL pers. comm.) and in 1 infant with LVH/RVH and other complex heart disease (GeneDx pers. comm.). This variant was identified in 0.0026% (FAF 95% CI; 3/30616) South Asian chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PM1.
GeneDx	RCV000158748	SCV000208683	uncertain significance	not provided	2022-03-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with cardiomyopathy in published literature, but familial segregation information and additional clinical information were not included (Homburger et al., 2016; Walsh et al., 2017); This variant is associated with the following publications: (PMID: 24865491, 27532257, 27247418, 28606303, 29687901, 27841901, 24111713, 23816408, 12707239, 29300372)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628868	SCV000749776	likely pathogenic	Hypertrophic cardiomyopathy	2023-10-29	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 204 of the MYH7 protein (p.Arg204Cys). This variant is present in population databases (rs397516259, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 36264615). ClinVar contains an entry for this variant (Variation ID: 181315). 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.Arg204 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707239, 23816408, 24111713, 24865491, 27247418, 27532257, 27841901). 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.
Ambry Genetics	RCV002354391	SCV002655450	uncertain significance	Cardiovascular phenotype	2023-10-20	criteria provided, single submitter	clinical testing	The p.R204C variant (also known as c.610C>T), located in coding exon 5 of the MYH7 gene, results from a C to T substitution at nucleotide position 610. The arginine at codon 204 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 detected in hypertrophic cardiomyopathy (HCM) cohorts, and in cohorts not selected for the presence of cardiomyopathy; however, clinical details were limited (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; Ganapathy A et al. J Neurol. 2019 Aug;266(8):1919-1926; Yoneda ZT et al. JAMA Cardiol. 2021 Dec;6(12):1371-1379; Park J et al. Hum Mol Genet. 2022 Mar;31(5):827-837). Another alteration at the same codon, p.R204H (c.611G>A), has been reported in association with HCM (Richard P et al. Circulation. 2003;107:2227-32). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002484984	SCV002779095	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-09-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998364	SCV004820449	uncertain significance	Cardiomyopathy	2023-09-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 204 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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 at least one individual affected with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 33495597). This variant has been identified in 6/282876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Arg204His, is known to be disease-causing (Clinvar variation ID: 43095), indicating that arginine at this position is important for MYH7 protein function. 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.