ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2945T>C (p.Met982Thr) (rs145532615)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited 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 (, 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, Partners HealthCare Personalized Medicine RCV000035834 SCV000059485 benign not specified 2018-02-02 criteria provided, single submitter clinical testing MYH7 c.2945T>C: Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in HGMD in 12 pa pers, with comments suggesting VUS since it has been seen in unaffected patients and those with other variants in cardiac genes. This variant is present in gnom AD at a frequency of 0.15% (189/126824 european chrs). It is classified in ClinV ar as VUS by 4 submitters (GeneDx, Ambry, CSER_CC_NCGL, Stanford), Likely benign by 2 (Invitae and Biesecker), and Likely pathogenic by CHEO.
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.
Invitae RCV000725743 SCV000254445 likely benign not provided 2019-02-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000247539 SCV000319156 uncertain significance Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725743 SCV000339116 uncertain significance not provided 2016-02-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000199809 SCV000386107 likely benign Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000292823 SCV000386108 likely benign Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000352353 SCV000386109 likely benign Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000401402 SCV000386110 likely benign Myosin storage myopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000279750 SCV000386111 likely benign Scapuloperoneal myopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000334844 SCV000386112 likely benign Myopathy, distal, 1 2016-06-14 criteria provided, single submitter clinical testing
Color RCV000758042 SCV000903365 likely benign Cardiomyopathy 2018-04-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000035834 SCV000917845 likely benign not specified 2018-10-16 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 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 0.0009 in 278896 control chromosomes, predominantly at a frequency of 0.0015 including 1 homozygote within the Non-Finnish European subpopulation in the gnomAD database and publications. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH7 causing the Cardiomyopathy phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, 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 (Clemente_2017). Furthermore, the variant has been reported in multiple affected individuals that carried other pathogenic variants such as MYBPC3 c.1504C>T, p.Arg502Trp; MYBPC3 c.2157_2158delTG, p.Cys719X; MYBPC3, p.Val219Phe, providing supporting evidence for a benign role (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. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant four times as likely benign/benign and three times as uncertain significance. 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 uncertain significance Left ventricular noncompaction criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000725743 SCV001149183 likely benign not provided 2018-10-01 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 (, 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.

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