ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2360G>A (p.Arg787His) (rs376754645)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 Familial 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".
Ambry Genetics RCV000250929 SCV000318690 uncertain significance Cardiovascular phenotype 2017-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
CSER_CC_NCGL; University of Washington Medical Center RCV000148708 SCV000190438 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000313839 SCV000564429 uncertain significance Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.2360G>A (p.Arg787His) variant has been reported in multiple individuals with hypertrophic cardiomyopathy; however >4 individuals carried a second variant sufficient to explain their disease (BP2; PMID:21959974; Partners LMM ClinVar SCV000059440.5; SHaRe consortium, PMID: 30297972). Additionally, this variant was identified in 0.1% (21/16512) of South Asian chromosomes (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 uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM1; BP2
Color RCV000776332 SCV000911684 likely benign Cardiomyopathy 2018-10-05 criteria provided, single submitter clinical testing
GeneDx RCV000035789 SCV000208466 likely benign not specified 2018-01-31 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago RCV000035789 SCV000248114 uncertain significance not specified 2015-04-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000348947 SCV000386155 likely benign Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000392228 SCV000386156 likely benign Myosin storage myopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000313839 SCV000386157 likely benign Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000354671 SCV000386158 likely benign Myopathy, distal, 1 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000392220 SCV000386159 likely benign Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000299638 SCV000386160 likely benign Scapuloperoneal myopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000313839 SCV000557944 likely benign Hypertrophic cardiomyopathy 2017-07-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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.
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
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).

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