Submissions for variant NM_000257.4(MYH7):c.2945T>C (p.Met982Thr)

gnomAD frequency: 0.00095  dbSNP: rs145532615

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000758042	SCV000564466	benign	Cardiomyopathy	2016-12-15	reviewed by expert panel	curation	The filtering allele frequency of the c.2945T>C (p.Met982Thr) variant in the MYH7 gene is 0.11% (88/66740) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372).
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148698	SCV000051409	likely benign	Increased left ventricular wall thickness	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035834	SCV000059485	benign	not specified	2024-04-11	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000035834	SCV000208515	benign	not specified	2019-03-22	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199809	SCV000254445	likely benign	Hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094109	SCV000386107	likely benign	Hypertrophic cardiomyopathy 1	2019-04-19	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	RCV000292823	SCV000386108	likely benign	Dilated cardiomyopathy 1S	2019-04-19	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	RCV000352353	SCV000386109	likely benign	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV003320058	SCV000386110	likely benign	Myosin storage myopathy	2019-04-19	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	RCV000334844	SCV000386112	likely benign	MYH7-related skeletal myopathy	2019-04-19	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.
Color Diagnostics, LLC DBA Color Health	RCV000758042	SCV000903365	likely benign	Cardiomyopathy	2018-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035834	SCV000917845	likely benign	not specified	2020-12-28	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.2945T>C (p.Met982Thr) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00085 in 253160 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is slightly higher than (approximately 1.12-fold) 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 Non-Finnish European origin. c.2945T>C has been reported in the literature in individuals affected with Cardiomyopathy, but also in controls, including in one family where the variant did not segregate with disease (e.g. Clemente_2017). Furthermore, the variant has been reported in multiple affected individuals that carried other pathogenic variants, including MYBPC3 c.1504C>T, p.Arg502Trp; MYBPC3 c.2157_2158delTG, p.Cys719X; MYBPC3, p.Val219Phe, providing supporting evidence for a benign role (e.g. Millat_Clinica Chimica Acta_2010, Millat_EJMG_2010, Ho_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 other ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments (uncertain significance, n=2; benign/likely benign, n=9). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845384	SCV000987444	benign	Left ventricular noncompaction	2020-06-21	criteria provided, single submitter	clinical testing	we reviewed this variant Benign in 2020, because of BA1
CeGaT Center for Human Genetics Tuebingen	RCV000725743	SCV001149183	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	MYH7: PP3, BS2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000758042	SCV001332831	benign	Cardiomyopathy	2018-01-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725743	SCV002506002	benign	not provided	2023-11-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433495	SCV002749991	likely benign	Cardiovascular phenotype	2018-08-01	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.
Fulgent Genetics, Fulgent Genetics	RCV002490487	SCV002803619	likely benign	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-07-30	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148698	SCV000190427	uncertain significance	Increased left ventricular wall thickness	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000035834	SCV000280338	uncertain significance	not specified	2015-02-11	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. p.Met982Thr (c.2945 T>C) in the MYH7 gene [NM_00257.2]. This variant has been reported in at least three individuals with HCM (two of which had an additional sarcomeric variant identified), 2-3 unrelated individuals with abnormal echocardiograms ascertained in the Framingham study, two individuals with DCM, and multiple individuals tested for cardiomyopathy at the testing lab (many with another variant considered pathogenic). Millat et al (2010) observed p.Met982Thr in two unrelated individuals with HCM, however, both of them had an additional variant in a sarcomere gene so the authors noted they could not rule out this variant as a rare benign variant. Morita et al (2006) looked for variants in genes associate with cardiomyopathy in individuals from the Framingham Heart Study who had LVWT > 13 mm and did not have hypertension. They observed p.Met982Thr in one of those individuals. Of note, they only found sarcomeric variants in 16% of this sample, this is lower than the ~40% yield that would be expected with the genes they examined and a sample of HCM patients. This would suggest that many individuals in this sample do not truly have HCM. They then looked for the variants they had identified in the first sample in a randomly collected sample of the Framingham Heart Study Offspring participants and identified p.Met982Thr in two reportedly unrelated individuals (unclear if one of them could be related to the first individual). The authors reported that one individual had an echocardiographic pattern consistent with "burnt out" cardiac hypertrophy with a dilated left ventricle (LV diastolic diameter >56 mm) and enlarged atrium, whereas the other had a mildly enlarged left atrium and ECG voltages suggestive of HCM. Both individuals were reported to normotensive. Mestroni et al (2010) in an ACC poster abstract reported this mutation in one individual with dilated cardiomyopathy from a DCM registry comprised of patients from Italy and the US. I also found a poster online from a German group that reported the variant in a patient with DCM (Waldmuller et al; their cohort seems to unique from the Mestroni et al cohort). In addition, I found a Spanish language online publication that appears to report the variant in an individual with HCM. Finally, this variant was identified in a recent paper from Gruner et al. 2011 in a patient with apical HCM. In this study, the authors screened 429 HCM probands for mutations in one of eleven genes associated with HCM (their panel included 8 sarcomere protein genes and 3 other genes (GLA, PRKAG2, and LAMP2)). This particular variant was identified in a male with apical HCM diagnosed at 18 years of age. The authors do not provide any specific details about the variant or control data. This proband reportedly had a family history of HCM; however the authors provided no specific details or segregation analysis, and defined “family history” as either documented evidence of HCM or by “highly convincing patient report”. No other variants have been reported in association with cardiomyopathy at codon 982 or nearby residues. The change is chemically non-conservative from a non-polar amino acid to a polar amino acid. The methionine at residue 982 is completely conserved across species, as are neighboring amino acids. In terms of in silico analysis, Polyphen predicts this variant to be probably damaging and Mutation Taster predicts this variant to be disease causing. In total, this particular variant has been seen in 22 of 7,003 published controls, laboratory controls, and publically available general population datasets. Morita et al. (2006) did not identify the variant in 300 presumably healthy controls of unspecified ethnicity. GeneDx has not identified the Met982Thr mutation in up to 200 control individuals of Caucasian and African American ancestry. Mestroni et al. (2010) mentioned having a control sample in their poster abstract, however details on the control sample size were not provided. The variant was reported online in 110 of 60,706 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of August 26th, 2015). The highest frequency was in Europeans with 88 of 33,370 individuals carrying the variant (MAF 0.13%). 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.
Eurofins Ntd Llc (ga)	RCV000725743	SCV000339116	uncertain significance	not provided	2016-02-03	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534741	SCV004728943	benign	MYH7-related disorder	2020-11-11	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).