ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1987C>T (p.Arg663Cys) (rs397516127)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620403 SCV000736283 pathogenic Cardiovascular phenotype 2018-02-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Blueprint Genetics RCV000157358 SCV000207096 pathogenic Primary familial hypertrophic cardiomyopathy 2014-09-17 no assertion criteria provided clinical testing
Blueprint Genetics RCV000158821 SCV000928236 pathogenic not provided 2019-02-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515169 SCV000611215 pathogenic Familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; Myopathy, distal, 1; Scapuloperoneal myopathy, MYH7-related 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000158821 SCV000208756 pathogenic not provided 2019-01-07 criteria provided, single submitter clinical testing The R663C pathogenic variant in the MYH7 gene has been previously reported in multiple unrelated individuals of various ethnic backgrounds with HCM (Van Driest et al., 2004; Song et al., 2005; Yu et al., Olivotto et al., 2011; Kubo et al., 2011; Kassem et al., 2013; Zou et al., 2013; Mook et al., 2013; Valente et al., 2013; Coppini et al., 2014) and has been observed in multiple other unrelated individuals referred for genetic testing for HCM at GeneDx. Additionally, R663C has been identified in 8 individuals with HCM and segregated with disease in 2 affected relatives by an external laboratory (SCV000059408.4; Landrum et al., 2016). This variant has also been classified as pathogenic or likely pathogenic by two other clinical laboratories in ClinVar (SCV000207096.1, SCV000219891.2).The R663C pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant results in a non-conservative amino acid substitution that occurs at a position where only amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, missense variants in the same residue (R663H, R663S) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), further supporting the functional importance of this residue.In summary, R663C in the MYH7 gene is interpreted as a pathogenic variant.
Invitae RCV000459608 SCV000546267 pathogenic Hypertrophic cardiomyopathy 2018-08-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 663 of the MYH7 protein (p.Arg663Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 15358028, 15563892, 23283745, 15858117, 22112859, 20800588, 23233322, 18383048, 23690394). ClinVar contains an entry for this variant (Variation ID: 42874). A different missense substitution at this codon (p.Arg663His) has been determined to be pathogenic (PMID: 10750581, 11133230). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. A computational algorithm designed to assess the pathogenicity of missense variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be pathogenic. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, this variant has been observed in several individuals affected with HCM, it is predicted to cause a deleterious effect on MYH7 protein function, for these reasons it has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000459608 SCV000059408 likely pathogenic Hypertrophic cardiomyopathy 2017-04-07 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
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.

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