Submissions for variant NM_000257.4(MYH7):c.1987C>T (p.Arg663Cys)

dbSNP: rs397516127

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000459608	SCV000059408	pathogenic	Hypertrophic cardiomyopathy	2019-06-26	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000158821	SCV000208756	pathogenic	not provided	2023-10-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21835320, 23690394, 27532257, 20800588, 30847666, 18383048, 23674513, 25714468, 25228707, 25351510, 23785128, 27247418, 15858117, 20350521, 23283745, 23233322, 25524337, 21799269, 15563892, 28606303, 27590665, 29497013, 29030401, 28193612, 29661763, 29743414, 27082122, 21310275, 22112859, 30775854, 32344918, 15358028, 32894683, 35653365, 35626289, 33673806, 32830170, 29300372)
Invitae	RCV000459608	SCV000546267	pathogenic	Hypertrophic cardiomyopathy	2024-01-29	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 663 of the MYH7 protein (p.Arg663Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 15358028, 15563892, 15858117, 18383048, 20800588, 22112859, 23233322, 23283745, 23690394). ClinVar contains an entry for this variant (Variation ID: 42874). 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.Arg663 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10750581, 11133230). 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.
Fulgent Genetics, Fulgent Genetics	RCV000515169	SCV000611215	pathogenic	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620403	SCV000736283	pathogenic	Cardiovascular phenotype	2021-03-09	criteria provided, single submitter	clinical testing	The p.R663C pathogenic mutation (also known as c.1987C>T), located in coding exon 16 of the MYH7 gene, results from a C to T substitution at nucleotide position 1987. The arginine at codon 663 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 numerous individuals with hypertrophic cardiomyopathy (HCM) from various ethnic groups (Van Driest SL et al, J. Am. Coll. Cardiol. 2004 Aug; 44(3):602-10; Yu B et al, J. Clin. Pathol. 2005 May; 58(5):479-85; Wang S et al, Clin Cardiol 2008 Mar; 31(3):114-8; Kassem HSh et al, J Cardiovasc Transl Res 2013 Feb; 6(1):65-80; Zhao Y et al. Int. J. Mol. Med., 2016 Jun;37:1511-20; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445). Additional alterations affecting the same amino acid, p.R663H (Gruver EJ et al, Am. J. Cardiol. 1999 Jun; 83(12A):13H-18H) and p.R663S (Richard P et al, Circulation 2003 May; 107(17):2227-32), were also reported in HCM patients, which may reflect a mutation hotspot at this position. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Klaassen Lab, Charite University Medicine Berlin	RCV000157358	SCV000995885	pathogenic	Primary familial hypertrophic cardiomyopathy	2019-07-03	criteria provided, single submitter	research
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170504	SCV001333087	pathogenic	Cardiomyopathy	2023-03-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000158821	SCV002017670	pathogenic	not provided	2022-04-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000158821	SCV002585459	pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	MYH7: PS4, PM2, PM5, PP2, PP3
Genetics and Molecular Pathology, SA Pathology	RCV000459608	SCV004175575	pathogenic	Hypertrophic cardiomyopathy	2023-01-16	criteria provided, single submitter	clinical testing	The MYH7 c.1987C>T variant is classified as Pathogenic (PS4, PM1, PM2, PP1_Moderate, PP3.) The MYH7 c.1987C>T variant is a single nucleotide change in exon 18/40 of the MYH7 gene, which is predicted to change the amino acid arginine at position 663 in the protein, to cysteine. This amino acid is within the conserved functional domain of the MYH7 protein where variation is expected to be disease causing (PM1). The variant has been reported in excess of 20 probands with a clinical presentation of Hypertrophic Cardiomyopathy (PMID#15358028, 33673806, 32344918, 30775854, 32894683, 35626289) (PS4) and is absent from population databases (PM2). This variant has been reported to segregate with disease (PMID #15563892, our cohort and SHaRE) (PP1_moderate). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs397516127) is reported as disease causing in the HGMD database (CM973126) and is reported as pathogenic by multiple other diagnostic laboratories (ClinVar #42874).
Color Diagnostics, LLC DBA Color Health	RCV001170504	SCV004356933	likely pathogenic	Cardiomyopathy	2022-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 663 in the myosin head/motor (S1) 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). 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 15 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 15563892, 15858117, 18533079, 20350521, 23674513, 27532257, 31568572). A different variant occurring at the same codon, p.Arg663His, is a well documented pathogenic mutation (Clinvar variation ID: 42875), 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.
Blueprint Genetics	RCV000157358	SCV000207096	pathogenic	Primary familial hypertrophic cardiomyopathy	2014-09-17	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158821	SCV000924863	pathogenic	not provided	2016-11-04	no assertion criteria provided	provider interpretation	The following genes were evaluated for sequence changes and exonic deletions/duplications (ACTC1, ACTN2, BAG3, CAV3, CSRP3, DES, ELAC2, FHL1, GLA, LAMP2, MTO1, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, TCAP, TNNC1, TNNI3, TNNT2, TPM1, TTR, VCL). The p.Arg663Cys (c.1987C>T) variant in the MYH7 gene was found. Given the strong case data, absence in controls, and presence of other pathogenic variants at the same codon, we classify this variant as very likely disease-causing (aka pathogenic). We feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We re-reviewed the variant November 4th, 2016. This variant is present in ClinVar. It is classified as likely pathogenic by 3 labs (LMM, GeneDx and the CHEO) and pathogenic by Blueprint. Case Data: The Arg663Cys variant has been previously reported in at least 19 presumably unrelated individuals with HCM. It segregates with at least 4 affected relatives (SHaRe) and possibly an additional 7 (Song et al. 2005). Van Driest 2004: This variant was present in 1 out of 389 patients with HCM from their Mayo cohort. The variant was absent in 200 control individuals Song 2005: This variant was present in 1 out of 100 unrelated Chinese patients with HCM. There may be strong published segregation data, although the paper is a bit unclear about how to interpret this data: they found Arg663Cys in one proband, but in Table 3 they describe 8 affected individuals showing 100% penetrance of Arg663Cys. They do not specify that all 8 individuals are from one family; however, they do indicate that individuals with this variant have a family history of sudden cardiac death and that two other family members died of HCM at a young age. This variant was absent in 120 control individuals. This report is presumably redundant with Zou et al 2013. Of note, Zou et al report that the patient had an additional variant in MYH7, p.Gln892Lys (Q892K). The Q892K variant is not reported in the literature, has not been seen in gnomAD and is predicted to alter a splice site. Yu 2005: This variant was present in 2 out of 150 unrelated Australian patients with HCM. The variant was absent in 100 ethnically-matched controls. Olivotto 2008: This variant was present in 1 out of 61 patients with HCM for their Florence cohort. This patient was a 45-year old male with a maximum LV wall thickness of 27mm. This variant was absent from 150 adult ethnically-matched controls. This may be redundant with the report by Coppini et al since both include patients from the Florence cohort. Hirota 2010: This variant was present in at least 1 out of 93 probands with HCM. It is unclear how many probands had this variant. Witjas-Paalberends 2013: This variant was present in 1 out of 43 probands with HCM. It is unclear where these patients were recruited from, however it is possible there is overlap with Mook et al 2013 as both studies have multiple authors from Amsterdam. Mook 2013: This variant was found in a patient with HCM from a clinical genetic testing cohort in amsterdam. Kassem 2013: This variant was found in 1 of 199 unrelated HCM patients from Egypt. The variant was not present in 100 healthy controls. Zhao et al 2016: This variant was found in 1 out of 8 patients with HCM from their Chinese cohort. This variant was absent from 100 control subjects. Based on authors and institutions this appears to be a distinct case from Song et al and Zou et al. In the SHaRe consortium the variant has been seen in the following unrelated HCM patients: three from the Yale cohort, three from the Michigan cohort, five from Florence, and one from Brigham and Women’s. Some of these cases overlap with Coppini et al, Olivotto et al, and the cases from the genetic testing laboratories. If we do not count laboratory data, then we can take 11 unique cases from the SHaRe dataset. There are also four affected relatives from various SHaRe sites who carry the variant. Other variants have been reported at this same codon: p.Arg663His (we and others consider pathogenic) and p.Arg663Ser (not reviewed by us, likely pathogenic by one submitter in ClinVar). Van Driest et al (2004) described codon 663 as a ‘hotspot’ with 9 out of 58 (15%) patients with MYH7 variants in that study having a variant that involved codon 663. Induced pluripotent stem cells (iPSCs) harboring this variant, obtained from a ten-member family cohort with HCM, recapitulated many aspects of the HCM phenotype including cellular enlargement and contractile arrhythmia at the single-cell level (Lan et al 2013). This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Cysteine capable of forming disulfide bridges. It is in the myosin head domain. This codon is enriched on the surface of the post-stroke motor domain, which is enriched for variation in patients with HCM. This indicates that this region in the myosin protein may be intolerant to genetic variation. Arginine at this location is highly conserved across vertebrate species (it is a Lysine in 2 species of bird). The adjacent residues are also highly conserved. In addition to variants at this residue (Arg663His, Arg663Ser), variation at nearby residues has also been associated with HCM, which supports the functional importance of this region of the protein: Arg652Gly, Leu658Val, Met659Ile, Met659Thr, Thr660Asn, His668Asn, Arg671Cys (HGMD professional version as of January 17, 2014). In silico analysis indicates that it is damaging to protein structure/function, according to GeneDx. LMM’s cardiomyopathy-specific algorithm agrees, according to ClinVar (Jordan et al, 2011). In total, the variant has not been seen in ~61,000 individuals from published control sets and databases approximating the general population. GeneDx reports that this variant is absent in at least 970 control individuals of various ethnic backgrounds in published control studies (Kassem et al., 2013; Mook et al 2013; Olivotto et al 2008; Song et al., 2005; Van Driest et al., 2004; Yu et al 2005- 100; Zhao et al 2016; Zou et al., 2013). This location is not well-covered in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/). However, it is well-covered Exome Aggregation Consortium Dataset (ExAC; http://exac.broadinstitute.org). This variant is absent in this dataset. This database currently includes variant calls on 60,706 unrelated individuals of African, Asian, European, Latino descent. The data includes 60,706 exomes (as of October 20, 2016). The average coverage at that site is more 65x.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000158821	SCV001739581	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000158821	SCV001919865	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000158821	SCV001958736	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000158821	SCV001965231	pathogenic	not provided		no assertion criteria provided	clinical testing