Submissions for variant NM_000257.4(MYH7):c.2360G>A (p.Arg787His)

gnomAD frequency: 0.00006  dbSNP: rs376754645

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000313839	SCV000564429	likely benign	Hypertrophic cardiomyopathy	2021-04-27	reviewed by expert panel	curation	The c.2360G>A (p.Arg787His) variant in MYH7 has been identified in 0.10% (FAF 95% CI; 41/30616) of South Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). Additionally, while 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; Walsh 2017 PMID:27532257), this pathogenic evidence code (PM1) was not considered to be in conflict with a likely benign conclusion. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1, PM1.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035789	SCV000059440	uncertain significance	not specified	2013-06-05	criteria provided, single submitter	clinical testing	The Arg787His variant has been reported in 7 probands (6 with HCM and 1 with DCM ), has been detected by our laboratory in 4 additional individuals with HCM. The majority of these individuals were of Indian or Arabic descent (Richard 2003, Y u 2005, Laredo 2006, Boda 2009, Rai 2009, Purushotham 2010; LMM unpublished data ). Three of 11 probands (2: LMM, 1: Laredo 2006) carried a second variant suffi cient to explain their disease. The variant was present in 1/4406 African Americ an chromosomes from a broad population screened by the NHLBI Exome Sequencing pr oject (http://evs.gs.washington.edu/EVS) but absent from 600 were race-matched c hromosomes (Purushotham 2010) and 600 additional chromosomes across several stud ies (Richard 2003, Yu 2005, Laredo 2006, Boda 2009, Rai 2009). Another variant a t the same position (Arg787Cys) has been reported in individuals with HCM (Morit a 2008, Garcia-Castro 2009); however, the affected amino acid (arginine) is only moderately conserved in evolution, suggesting that a change may be tolerated or be milder. A milder effect was also suspected by Purushotham 2010 who detected the variant in 2 affected individuals but also 8 asymptomatic relatives. Of not e, one of these families had a history of sudden death including the son of an i ndividual who tested negative for the Arg787His variant. While a phenocopy cann ot be ruled out this possible non-segregation raises concern regarding the patho genicity of the Arg787His variant. In summary, the data for this variant is some what conflicting and additional studies are needed to clarify its role in diseas e.
GeneDx	RCV001705651	SCV000208466	likely benign	not provided	2021-02-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17125710, 29343710, 20086309, 12707239, 31006259, 20664766, 20433692, 21959974, 22957257, 23299917, 25228707, 25637381, 27247418, 28518168, 30731207, 29300372, 30847666, 31638223)
Genetic Services Laboratory, University of Chicago	RCV000035789	SCV000248114	uncertain significance	not specified	2015-04-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000250929	SCV000318690	likely benign	Cardiovascular phenotype	2022-06-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000348947	SCV000386155	likely benign	Dilated cardiomyopathy 1S	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV003320055	SCV000386156	likely benign	Myosin storage myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000584813	SCV000386157	likely benign	Hypertrophic cardiomyopathy 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000354671	SCV000386158	likely benign	MYH7-related skeletal myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000392220	SCV000386159	likely benign	Left ventricular noncompaction cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000313839	SCV000557944	likely benign	Hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000035789	SCV000604365	uncertain significance	not specified	2016-12-09	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000584813	SCV000692500	likely benign	Hypertrophic cardiomyopathy 1	2017-03-10	criteria provided, single submitter	research	The MYH7 Arg787His variant occurs in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.02%. In silico tools (SIFT, PolyPhen-HCM, MutationTaster) are in support of a benign role. The MHY7 Arg787His variant was identified in a HCM proband with no family history of disease. The proband also harbours 2 additional MYBPC3 variants (p.Ala693Val & p.Arg817Gly) that are likely contributing to the disease phenotype. A second individual with non-diagnostic hypertrophy was also identified with this variant. Based on the high frequency in the general population and in silico tool predicting a benign effect, we classify MYH7 Arg787His as "likely benign".
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000148708	SCV000740370	uncertain significance	Primary familial hypertrophic cardiomyopathy	2017-06-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776332	SCV000911684	likely benign	Cardiomyopathy	2018-10-05	criteria provided, single submitter	clinical testing
Mendelics	RCV000584813	SCV001139415	benign	Hypertrophic cardiomyopathy 1	2023-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035789	SCV001360966	uncertain significance	not specified	2019-07-15	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.2360G>A (p.Arg787His) results in a non-conservative amino acid change located in the Myosin head, motor domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251472 control chromosomes, predominantly at a frequency of 0.0013 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.039 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH7 causing Cardiomyopathy phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2360G>A has been reported in the literature in multiple individuals affected with Cardiomyopathy. However, the variant has also been observed in multiple families that showed lack of cosegregation with disease including unaffected individuals with the variant and affected individuals without the variant (Purushotham_2010, Laredo_2006). In addition, the variant has been observed to co-occur with other pathogenic variants, MYBPC3 c.3641G>A, p.W1214X; MYH7, I736T), providing supporting evidence for a benign role. A functional study, Sequeira_2013, indicates the variant to have higher Ca 2+ sensitivity and low phosphorylation of protein kinase A targets compared to donors, along with length-dependent activation being significantly smaller. Ten ClinVar submissions (evaluation after 2014) cite the variant five times as likely benign, while five other submissions including the expert panel, ClinGen, cite the variant as uncertain signfiicance. In addition, another variant affecting the same codon, R787C, has been reported in affected individuals suggesting the location could be important for protein function. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000776332	SCV002042269	likely benign	Cardiomyopathy	2020-10-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001705651	SCV004237856	likely benign	not provided	2022-12-21	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148708	SCV000190438	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000035789	SCV000280321	uncertain significance	not specified	2014-01-29	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. MYH7 p.Arg787His We consider this a variant of uncertain significance, likely disease causing, based on the co-occurrence of another pathogenic variant in several of the cases with multi-gene sequencing and the possible failure to segregate in one family. The variant has been seen in at least 9 unrelated cases of cardiomyopathy (not including the patient). Three patients had another variant sufficient to explain their disease. Five of the other cases had insufficient sequencing to determine if another variant was present. There is weak segregation data in two families, though in one of them there is potential for failure to segregate with insufficient information available. Richard P et al., 2003 first described this variant in a European individual with HCM. They sequenced 9 genes (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, TPM1, ACTC and TNNC1) in 197 unrelated index cases with HCM. Patients were recruited from France and most of them were of European origin. No details regarding this patient's phenotype was given. Yu et al (2005) observed the variant in one of 150 patients with HCM from their Australian cohort. They reported only on analysis of MYH7. Laredo et al (2006) reported this variant in a 43 year old Spanish female, who also harbored p.Ile736Thr variant in the MYH7 gene (which we classify as likely disease causing). They sequenced MYH7 in 128 patients with HCM to compare the phenotypes of those with and without mutations in MYH7. The patient who harbored this variant in addition to the p.Ile736Thr variant in MYH7 was a female diagnosed at age 43 with a maximum thickness of 30mm and asymmetric hypertrophic morphology. The patient's mother was diagnosed with HCM at age 43 and had undergone a myectomy and died from heart failure at age 69. It appears that the father tested negative for both variants. The patient's sons both inherited only the p.Ile736Thr variant, revealing that these variants were in trans. Her eldest son had some hypertrophy with maximal thickness of 11mm at age 21. Her youngest son had maximal thickness of 13mm with asymmetric hypertrophy at age 16. None of the studied family members had just p.Arg787His. Boda et al (2009) observed the variant in one of 100 idiopathic DCM cases in their Indian cohort. They analyzed MYH7, TNNI3, ACTC. Rai et al (2009) observed the variant in one of 69 patients with HCM in their Indian cohort. They only analyzed MYH7. Purushotham et al. (2010) reported this variant in two unrelated Indian patients with HCM. The authors sequenced exons 3-23 of the MYH7 gene and all exons of the MYBPC3 gene. The authors did not sequence other genes in the patients identified to carry the p.Arg787His variant. In each family there were two affected first degree relatives who carry the variant. Of note, in one of these families there was an "uninvestigated sudden death" in the child of someone who tested negative for the variant, suggesting a possible failure to segregate. This variant is located in exon 21 of the MYH7 gene. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The arginine at codon 787 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Arg787Cys) and nearby codons (Ser782Asn; Arg783His, Arg793Gln). Purushotham and colleagues presented some functional data which suggested that this substitution is not tolerated. Sequence and structure analysis of the MYH7 mutation revealed that the mutant protein might be compromised in its ability to bind essential light chain efficiently. The authors suggested that the MYH7 p.Arg787His variant may result in mild clinical symptoms similar to other mutations that occur in the neck region of the protein. In total the variant has been seen in 1 of 7003 published controls and individuals from publicly available population datasets. The variant was reported online in 0 of 4300 Caucasian individuals and 1 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of 2/6/14). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). Note that this dataset does not match the patient's ancestry (Chinese) or the ancestry of about half of the cases (Indian). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 2/5/14). The variant was not observed in the following published control samples: 100 control individuals (Richard et al 2003), 100 control individuals (Purushotham et al 2010), 100 control individuals (Yu et al 2005), 100 control individuals (Boda et al 2009), 100 control individuals (Rai et al 2009).
Clinical Genetics, Academic Medical Center	RCV001705651	SCV001919667	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001705651	SCV001928253	uncertain significance	not provided		no assertion criteria provided	clinical testing