Submissions for variant NM_000257.4(MYH7):c.2080C>T (p.Arg694Cys)

gnomAD frequency: 0.00001  dbSNP: rs727504240

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000628970	SCV000203858	likely pathogenic	Hypertrophic cardiomyopathy	2019-09-19	criteria provided, single submitter	clinical testing	The p.Arg694Cys variant in MYH7 has been reported in at least 11 individuals with HCM and segregated with disease in 3 affected relatives from 2 families (Andersen 1999 and 2004, Van Driest 2004, Witjas-Paalberends 2013, Alfares 2015, GeneDx pers comm, LMM data). At least 4 individuals carried additional likely disease causing variants in the MYBPC3 gene (Van Driest 2004, GeneDx pers comm). In addition, this variant has been identified in 5/251358 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variant ID: 177627). Computational prediction tools and conservation analyses suggest that this 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, and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). 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_Moderate, PM1, PM2, PP3, PP1.
GeneDx	RCV001723720	SCV000208441	likely pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	Identified in several individuals with HCM in published literature, though some of these individuals also harbored reportedly pathogenic variants in other HCM-related genes (PMID: 10563488, 15519027, 18533079, 27532257, 32894683); Identified independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx, and it was observed to segregate with cardiomyopathy in at least one family member; 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: 26688388, 21310275, 34542152, 31737537, 32528171, 23197161, 24928957, 18533079, 18761664, 20031602, 25524337, 12566107, 15114369, 15519027, 27532257, 15358028, 25611685, 20819418, 28606303, 27247418, 23674513, 32894683, 32369506, 31323898, 10563488, 29300372, 37652022, 36264615)
Ambry Genetics	RCV000618360	SCV000740227	likely pathogenic	Cardiovascular phenotype	2024-11-05	criteria provided, single submitter	clinical testing	The p.R694C variant (also known as c.2080C>T), located in coding exon 17 of the MYH7 gene, results from a C to T substitution at nucleotide position 2080. The arginine at codon 694 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 alteration has been reported in multiple individuals with features consistent with hypertrophic cardiomyopathy (HCM) (Andersen PS et al. Eur. J. Hum. Genet., 2004 Aug;12:673-7; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Walsh R et al. Genet. Med., 2017 02;19:192-203; Ho CY et al. Circulation, 2018 10;138:1387-1398). Another variant at the same codon, p.R694H (c.2081G>A), has also been reported in association with HCM (Erdmann J et al. Clin Genet. 2003;64(4):339-49; Berge KE and Leren TP. Clin Genet. 2014;86(4):355-60; Lopes LR et al. Heart. 2015;101(4):294-301; external communication; Ambry internal data).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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628970	SCV000749880	pathogenic	Hypertrophic cardiomyopathy	2025-01-16	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 694 of the MYH7 protein (p.Arg694Cys). This variant is present in population databases (rs727504240, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10563488, 12566107, 15114369, 15519027, 22811549, 23674513, 25611685, 27247418, 27532257, 31737537, 32894683; internal data). ClinVar contains an entry for this variant (Variation ID: 177627). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). This variant disrupts the p.Arg694 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 12974739, 20819418), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000628970	SCV000786691	pathogenic	Hypertrophic cardiomyopathy	2024-09-04	criteria provided, single submitter	research	The heterozygous p.Arg694Cys variant in MYH7 was identified by our study in 1 individual with Laing early-onset distal myopathy (PMID: 32528171). This variant is assumed de novo in the individual, but maternity and paternity have not been confirmed. The p.Arg694Cys variant in MYH7 has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 10563488, 15519027, 18761664, 32369506) and has been identified in 0.007% (2/29608) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504240). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Pathogenic variants may be present at a low frequency in the general population, for diseases with clinical variability, or reduced penetrance. This variant has also been reported in ClinVar (Variation ID: 177627) and has been interpreted as pathogenic and likely pathogenic by multiple submitters. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg694His, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 264068). Multiple variants in the same region as p.Arg694Cys have been reported in association with disease in the literature and ClinVar, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 27532257). The number of missense variants reported in MYH7 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. Although this variant was identified in our study in a proband with Laing early-onset distal myopathy, there is insufficient evidence to also associate the variant with this condition. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant hypertrophic cardiomyopathy. ACMG/AMP Criteria applied: PP3_moderate, PM5, PS4_moderate, PP2, PM1_supporting (Richards 2015).
Color Diagnostics, LLC DBA Color Health	RCV003531980	SCV004356930	likely pathogenic	Cardiomyopathy	2022-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 694 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 15 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 10563488, 15519027, 18533079, 23674513, 24793961, 25524337, 27247418, 27532257, 32228044, 32369506), including 5 of them who also carried a pathogenic variant in the MYBPC3 gene (PMID: 15519027, 18533079, 32228044). It has been shown that this variant segregates with disease in 5 affected individuals in a family (PMID: 10563488, 15114369, 19035361). This variant has also been reported in an individual affected with unexplained limb-girdle weakness (PMID: 32528171). This variant has been identified in 5/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000628970	SCV005045731	likely pathogenic	Hypertrophic cardiomyopathy	2023-12-27	criteria provided, single submitter	clinical testing	The c.2080C>T (p.Arg694Cys) variant in MYH7 gene, that encodes for myosin heavy chain 7, has been identified in several (>10) unrelated individuals affected with the consistent phenotype of hypertrophic cardiomyopathy (HCM) (PMID:15358028, 23674513, 25611685, 27532257, 32894683, 22811549, 32369506, 27247418, 24793961, 31737537) and segregated with disease in three affected individuals including the proband in one family (PMID: 10563488). This variant lies in the established functional domain (amino acids 181-937) of the MYH7 protein without benign variations and missense variants in this region are statistically more likely to be disease-associated (PMID:27532257, 27247418). In-silico computational prediction tools suggest that the p.Arg694Cys variant may have deleterious effect on the protein function (REVEL score: 0.81). This variant is rare (5/251358 chromosomes; 0.001989%) in the general population database, gnomAD. It is interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ID: 177627). Another missense substitution affecting the same amino acid, p.Arg694His, has been reported in several (>10) individuals with HCM and classified as likely pathogenic/pathogenic by several submitters in ClinVar (ID: 264068). Therefore, the c.2080C>T (p.Arg694Cys) variant in the MYH7 gene is classified as likely pathogenic.
All of Us Research Program, National Institutes of Health	RCV000628970	SCV005431120	likely pathogenic	Hypertrophic cardiomyopathy	2024-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 694 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 15 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 10563488, 15519027, 18533079, 23674513, 24793961, 25524337, 27247418, 27532257, 32228044, 32369506), including 5 of them who also carried a pathogenic variant in the MYBPC3 gene (PMID: 15519027, 18533079, 32228044). It has been shown that this variant segregates with disease in 5 affected individuals in a family (PMID: 10563488, 15114369, 19035361). This variant has also been reported in an individual affected with unexplained limb-girdle weakness (PMID: 32528171). This variant has been identified in 5/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786922	SCV000925823	likely pathogenic	Hypertrophic cardiomyopathy 1	2018-12-12	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723720	SCV001953165	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001723720	SCV001963370	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723720	SCV001969066	pathogenic	not provided		no assertion criteria provided	clinical testing