ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2609G>A (p.Arg870His) (rs36211715)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000233703 SCV000564434 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.2609G>A (p.Arg870His) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:7796500; PMID:12974739; PMID:17703256; PMID:27532257; Partners LMM ClinVar SCV000059458.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >10 affected individuals (PP1_Strong; PMID:7796500; PMID:12974739; PMID:17703256). This variant was identified in 1/66732 European chromosomes (PM2; http://exac.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 disease-associated (PM1; PMID:27532257). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000233703 SCV000059458 pathogenic Hypertrophic cardiomyopathy 2018-07-25 criteria provided, single submitter clinical testing The p.Arg870His variant in MYH7 has been reported in >15 individuals with HCM an d segregated with disease in >15 affected relatives (Nishi 1995, Erdmann 2003, T anjore 2006, Laredo 2006, Bashyam 2007, Garcia-Castro 2009, Capek 2011, Santos 2 012, Zou 2013, Meyer 2013, LMM data). This variant has been identified in 2/1266 74 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org/; dbSNP rs36211715). In vitro studies provide additional ev idence that the p.Arg870His variant impacts protein function (Cuda 1997, Gruen 1 999). In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon number of probands, segregation studies, and functional evidence. ACMG/AMP Criteria applied: PS4; PP1_Strong; PP 3; PM2; PS3_Supporting.
Blueprint Genetics RCV000157361 SCV000207099 pathogenic Primary familial hypertrophic cardiomyopathy 2015-04-23 criteria provided, single submitter clinical testing
GeneDx RCV000158555 SCV000208490 pathogenic not provided 2018-08-03 criteria provided, single submitter clinical testing The R870H pathogenic variant in the MYH7 gene has previously been reported several times in association withHCM and was observed to segregate with disease in multiple unrelated families (Nishi et al., 1995; Watkins et al.,1995; Cuda et al., 1997; Erdmann et al., 2003; Laredo et al., 2006; Bashyam et al., 2007; Garcia-Castro et al., 2009;Kaski et al., 2009; Capek et al., 2011; Coto et al., 2012; Santos et al., 2012; Zou et al., 2013; Berge et al., 2014).Bashyam et al. (2007) identified several members of a consanguineous Indian family with HCM who wereheterozygous for R870H, and also a single individual with a more severe clinical phenotype who was homozygous forR870H and died at the age of 36 years. The R870H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al.,2015; Exome Variant Server). Although the R870H variant is a conservative amino acid substitution, thissubstitution occurs at a residue within the beta-myosin heavy chain where only amino acids with similar properties toArginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. Functional studies by Cuda et al. (1997) and Gruen et al. (1999) demonstrated that R870H impactsmyosin protein function and drastically reduces myosin binding to MYBPC3. Finally, multiple missense variants innearby residues (S866P, S866Y, A868P, R869G, R869C, R869H, L873P) and different missense variants at the sameresidue (R870C, R870L) 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 and region of the protein.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000015177 SCV000223879 pathogenic Familial hypertrophic cardiomyopathy 1 2015-04-09 criteria provided, single submitter research This MYH7 Arg870His variant has been previously well described in multiple unrelated HCM cases (see references). Segregation of this variant with disease has been demonstrated in multiple unrelated families (Nishi H, et al., 1995; Erdmann J, et al., 2003; Tanjore RR, et al., 2006; Bashyam MD, et al., 2007), with incomplete penetrance observed in a few individuals. Two affected individuals who are homozygous for this variant have been identified in a large consanguineous family amongst other members who were heterozygous for MYH7 Arg870His (Tanjore RR, et al., 2006; Bashyam MD et al., 2007). We have identified this variant in one case with familial HCM. Familial segregation has identified the variant to be present in 2 clinically affected siblings. This variant is rare and is only observed as a singleton event in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Arginine (Arg) at position 870 is highly conserved across distantly related species. Interestingly, there have been implications that other amino acid substitutions at this location (Arg870Cys, Arg870Leu) are causative of HCM, however, pathogenicity for these variants have not yet been fully established. Based on the rarity of the variant in the general population, observations in multiple unrelated HCM cases, and evidence of segregation with disease, we classify MYH7 Arg870His as "pathogenic".
Invitae RCV000233703 SCV000284268 pathogenic Hypertrophic cardiomyopathy 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 870 of the MYH7 protein (p.Arg870His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. While this variant is present in population databases (rs36211715, ExAC), the frequency information is unreliable due to low sequence quality at this site. This variant has been reported in several families segregating with disease (PMID: 12974739, 17703256, 7796500) and in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 21674835, 19150014, 24111713, 7796500, 10725281, 23283745, 22429680, 23816408, 17125710, 20031618, 27532257). ClinVar contains an entry for this variant (Variation ID: 14120). One experimental study has shown that this missense change in an in vitro motility assay moved actin filaments more slowly than control samples (PMID: 9172070). In addition, studies on the structural properties of the MYH7 protein has suggested that this variant reduces the protein binding affinity (PMID: 17192269). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626634 SCV000747335 pathogenic Hypertrophic cardiomyopathy; Chest pain 2017-01-01 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000015177 SCV000840021 pathogenic Familial hypertrophic cardiomyopathy 1 2017-07-10 criteria provided, single submitter clinical testing This c.2609G>A (p.Arg870His) has peviously been reported in several patients [PMID 8541871, 17703256, 21674835, 23816408]. Among them, the variant was detected in a large family: 19 individuals were tested and the variant segegated in all 14 affected family members [PMID 17703256]. One of these individual was homozygous for the variant and severely affected. Additional in vitro studies showed that this variant affects the function of the MYH7 protein by impacting its interaction with MYBPC3 [PMID 9172070, 10024460]. Structural modeling predicts the region harboring the p.Arg870His to affect the structure and function of the protein [PMID 21674835]. Other variants reported in patients with HCM and affecting the same amino acid have been reported (p.Arg870Cys, p.Arg870Leu). Arginine at position 870 of the MYH7 protein is conserved among mammals and computer-based algorithms SIFT and Polyphen-2 predict this p.Arg870His change to be deleterious. Next generation sequencing (NGS) reads indicated a skewed mutant to reference allele ratio (about 14% mutant), which was confirmed by Sanger sequencing, indicating mosaicism in the blood sample of this individual. We are not aware of any previously reported patient with a mosaic finding in MYH7. Therefore, the clinical significance of this finding is unknown at this time. The level of mosaicism may differ between this blood sample and cardiomyocytes in this patient. In addition, germline mosaicism cannot be excluded. Thus, clinical correlation and studies in family members at risk is recommended.
Center for Human Genetics,University of Leuven RCV000233703 SCV000886790 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000015177 SCV000035434 pathogenic Familial hypertrophic cardiomyopathy 1 2006-05-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158555 SCV000280330 pathogenic not provided 2015-02-26 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Arg870His (R870H; c.2609G>A) This variant has been reported in at least 11 unrelated cases of HCM with strong segregation data in one SE-Asian Indian family (11 individuals), good segregation data in 2 additional families, and weak segregation data in two more. Structural and functional data are available. Rayment et al. (1995) first mentioned this variant, but referred to it as still “unpublished”. Nishi et al. (1995) found it in a Japanese compound heterozygote, who also carried an MYH7 Arg54ter mutation. The Arg870His variant was also present in the patient’s affected father, but not the Arg54ter (which came from the patient’s unaffected mother and grandmother). This group also found Arg870His in 2 additional families. It segregated with HCM in 5 members of one family (including 4th degree relatives) and a parent and child in the other. Koga et al. (1996) reported this variant in 3 separate Japanese families. The variant was “present in all affected family members” (a total of 9 people), but specific segregation data is not provided. Erdmann et al. (2003) detected it in 2 unrelated German HCM cases. In one family, it segregated with disease in 4 affected family members (all siblings); the LOD score was +1.45. Tanjore et al. (2006) detected the variant in 2 unrelated SE-Asian Indian families. Strong segregation data is available in one of those families. The variant segregated with disease in 11 affected family members, several of them second-cousins (5th degree relatives). This pedigree contained consanguinity in every generation diagrammed, and two family members were homozygotes for Arg870His. Capek et al. (2011) found the variant in a Czech HCM patient. There is structural and functional data available: Cuda et al. (1997) took muscle biopsies from HCM patients with this variant, and showed that the mutant cardiac myosin has abnormal function in an in vitro assay in which actin filaments are translocated by myosin bound to a coverslip surface. Gruen & Gautel (1999) showed the variant to significantly reduce myosin binding to MYBPC. Muraishi et al. (1999) took endomyocardial biopsies from 2 patients with the variant, and found disrupted alignment of sarcomeric filaments under electron microscopy. Other changes at this same codon, Arg870Cys (Woo et al. 2003) and Arg870Leu, have been associated with HCM (Harvard Sarcomere Protein Gene Mutation Database). Variation at nearby loci of MYH7 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Ser866Tyr, Arg869Cys, Arg869Gly, Arg869His, and Met877Lys (Harvard Sarcomere Protein Gene Mutation Database). This is a conservative amino acid change from a basic, positively-charged Arginine to a basic, positively-charged Histidine. The Arginine at codon 870 is highly conserved across 40 vertebrate species examined (it is a lysine in 2 species: Stickleback and Tetraodon). Surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “possibly damaging”. This variant is in the rod domain of the beta-myosin heavy chain protein (Rayment et al. 1995), localized to the coiled-coil alpha-helical S-2 region (Cuda et al. 1997). The Arg870His variant is present in dbSNP as rs36211715 (“probable-pathogenic”). It was submitted by the Dept. of Genetics at Osmania University, and also by the OMIM staff at Johns Hopkins. In total this specific variant has not been seen in ~5670 published controls and publicly available population datasets. It is not present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012) or in 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Nishi et al. (1995) did not detect it in 220 Japanese controls. Koga et al. (1996) did not detect the variant in more than 100 Japanese controls. Erdmann et al. (2003) did not detect it in 50 German controls. However, a different variation at codon 870 is listed in the NHLBI Exome Sequencing Project dataset: Arg870Cys. This was present in 1/3510 Caucasian individuals and 0/1869 African American individuals (as of 1/15/2012). It is listed in dbSNP as rs138049878, and was submitted by NHLBI-ESP.

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