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

gnomAD frequency: 0.00001  dbSNP: rs36211715

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen 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, Mass General Brigham Personalized Medicine	RCV000233703	SCV000059458	pathogenic	Hypertrophic cardiomyopathy	2020-10-05	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Blueprint Genetics	RCV000157361	SCV000207099	pathogenic	Primary familial hypertrophic cardiomyopathy	2015-04-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000158555	SCV000208490	pathogenic	not provided	2022-02-14	criteria provided, single submitter	clinical testing	Functional studies demonstrated that p.(R870H) affects myosin protein function and drastically reduces myosin binding to myosin-binding protein C (MyBP-C) (Cude at al., 1997; Gruen et al., 1999); 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; Reported in ClinVar as pathogenic by the ClinGen Inherited Cardiomyopathy Expert Panel (ClinVar Variant ID# 14120; ClinVar); This variant is associated with the following publications: (PMID: 22765922, 23816408, 27247418, 10725281, 8541871, 24111713, 16650083, 22429680, 12974739, 21310275, 7796500, 23283745, 19150014, 10024460, 28166811, 27532257, 21674835, 28420666, 28481356, 28606303, 29030401, 8483915, 17192269, 23074333, 29565423, 7731997, 25611685, 29300372, 17125710, 20031618, 31447099, 31737537, 31513939, 30847666, 33673806, 32746448, 34051236, 34067482, 32894683, 33087929, 17703256, 9172070)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000015177	SCV000223879	pathogenic	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".
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233703	SCV000284268	pathogenic	Hypertrophic cardiomyopathy	2025-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 870 of the MYH7 protein (p.Arg870His). This variant is present in population databases (rs36211715, gnomAD 0.002%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 7796500, 10725281, 12974739, 17125710, 17703256, 19150014, 20031618, 21674835, 22429680, 23283745, 23816408, 24111713, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14120). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 9172070, 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	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
Genomics England Pilot Project, Genomics England	RCV000015177	SCV001760333	likely pathogenic	Hypertrophic cardiomyopathy 1		criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000158555	SCV001905614	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000158555	SCV002501757	pathogenic	not provided	2022-01-06	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000015177	SCV002549735	pathogenic	Hypertrophic cardiomyopathy 1		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000158555	SCV002822124	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	MYH7: PS3, PS4, PP1, PP2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000157361	SCV004030125	pathogenic	Primary familial hypertrophic cardiomyopathy	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.2609G>A (p.Arg870His) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251430 control chromosomes (gnomAD). c.2609G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (examples: Koga_1996, Atiga_2000, Laredo_2006, Tanjore_2006). These data indicate that the variant is very likely to be associated with disease. Multiple reports have shown that this variant impairs normal activity of the protein (examples: Cuda_1997 and Gruen_1999). Fourteen submitters (including ClinGen Cardiomyopathy Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000233703	SCV004822512	pathogenic	Hypertrophic cardiomyopathy	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 870 of the MYH7 protein. Computational prediction suggests that this variant may have a 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 over 50 individuals affected with hypertrophic cardiomyopathy (PMID: 7796500, 9172070, 10725281, 12974739, 16650083, 17125710, 17703256, 19150014, 20031618, 21674835, 22429680, 22765922, 23283745, 23816408, 24111713, 24793961, 25132132, 25351510, 25611685, 27532257, 27885498, 28408708, 28615295, 28790153, 29875424, 30847666, 31513939, 31737537, 32746448, 33029862, 33673806, 35288587). It has been shown that this variant segregates with disease in multiple affected individuals across several large families (PMID: 7796500, 12974739, 16650083, 17703256). It has also been reported in an individual affected with arrhythmogenic cardiomyopathy (PMID: 34067482). This variant has been identified in 2/282808 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg870Cys, is considered to be disease-causing (ClinVar variation ID: 161326), suggesting that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV004595882	SCV005091087	likely pathogenic	Dilated cardiomyopathy 1S	2024-04-11	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP3, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 14120). This variant has been previously reported as causative (PMID:16650083).
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000158555	SCV005199392	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	RCV000015177	SCV005374710	pathogenic	Hypertrophic cardiomyopathy 1	2024-07-31	criteria provided, single submitter	clinical testing	PM1_Mod PM2 PP1_Str PP3_Supp PS4_Str
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000015177	SCV005398831	pathogenic	Hypertrophic cardiomyopathy 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (6 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is found within the head region, which is enriched with pathogenic missense variants (PMID: 29300372). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a well reported pathogenic variants in individuals with hypertrophic cardiomyopathy (ClinVar, PMID: 28408708). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000015177	SCV000035434	pathogenic	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.
Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University	RCV001731289	SCV001573216	pathogenic	Arrhythmogenic cardiomyopathy	2021-04-27	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000158555	SCV001744898	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000158555	SCV001923335	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000158555	SCV001952081	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000158555	SCV001970213	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004757109	SCV005350791	pathogenic	MYH7-related disorder	2024-05-07	no assertion criteria provided	clinical testing	The MYH7 c.2609G>A variant is predicted to result in the amino acid substitution p.Arg870His. This variant was reported in several individuals with hypertrophic cardiomyopathy (Table S1. Weissler-Snir et al. 2017. PubMed ID: 28193612; File S3. van Lint et al. 2019. PubMed ID: 30847666; Table S1. Robyns et al. 2019. PubMed ID: 31513939; Table S1. Marschall et al. 2019. PubMed ID: 31737537; Table S2. Burstein et al. 2020. PubMed ID: 32746448; Table 1. Hathaway et al. 2021. PubMed ID: 33673806; e Table 3. Guo et al. 2021. PubMed ID: 34076677; Table S1. Lesurf et al. 2022. PubMed ID: 35288587; Table S1. Stava et al. 2022. PubMed ID: 35653365). In vitro experimental studies suggest this variant impacts protein function (Table S3. Kelly et al. 2018. PubMed ID: 29300372; Singh et al. 2021. PubMed ID: 34051236). This variant is reported in 0.0015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.