ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.4136C>T (p.Thr1379Met)

gnomAD frequency: 0.00036  dbSNP: rs145611185
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000216382 SCV000272024 uncertain significance not specified 2015-08-06 criteria provided, single submitter clinical testing The p.Thr1379Met variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (72/66714) of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs145611185). Computational prediction tools and conservation analysis suggest that the p.Thr1379Met variant may impact the protein, though this infor mation is not predictive enough to determine pathogenicity. In summary, the clin ical significance of the p.Thr1379Met variant is uncertain.
Invitae RCV000989182 SCV000287422 likely benign Hypertrophic cardiomyopathy 14 2024-01-19 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000216382 SCV000740618 likely benign not specified 2016-11-25 criteria provided, single submitter clinical testing
Mendelics RCV000989182 SCV001139403 benign Hypertrophic cardiomyopathy 14 2023-08-22 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001171183 SCV001333875 benign Cardiomyopathy 2017-12-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000216382 SCV001360445 benign not specified 2019-01-28 criteria provided, single submitter clinical testing Variant summary: MYH6 c.4136C>T (p.Thr1379Met) 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 0.00056 in 277218 control chromosomes, predominantly at a frequency of 0.0011 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 approximately 44 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4136C>T has been reported in the literature in affected individuals (Preuss_2016, Tomita-Mitchell_2016, Hertz_2015, Jia_2015, Theis_2015, Blue_2014, Posch_2011) without strong evidence of causality while, it was documented to not co-segregate with disease (Theis_2015, Blue_2014). Furthermore, it was identified in at-least two families with congenital heart defects where an alternate molecular basis of disease, namely segregating mutations in the TBX5 gene, causative of Holt-Oram syndrome were identified (Blue_2014, Jia_2015). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (2x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
GeneDx RCV000233729 SCV001820912 likely benign not provided 2020-09-01 criteria provided, single submitter clinical testing Observed in a family with CHD; however, a nonsense variant in the TBX5 gene was also identified and was found to segregate with disease in this family, while the T1379M variant did not segregate with disease (Blue et al., 2014); Identified in an individual with Brugada syndrome (Hertz et al., 2016); Published in association with autosomal recessive pattern of inheritance in the literature after identifying the T1379M variant in an individual with hypoplastic left heart syndrome who harbored another variant on the opposite MYH6 allele (in trans) (Theis et al. 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar with conflicting classfications (ClinVar Variant ID 180425; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32880476, 32277046, 30847666, 27789736, 27760138, 26085007, 25500235, 20656787, 25467552)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000233729 SCV002049100 likely benign not provided 2020-11-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV002326893 SCV002628904 likely benign Cardiovascular phenotype 2019-09-16 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.
Blueprint Genetics RCV000157339 SCV000207076 uncertain significance Primary familial hypertrophic cardiomyopathy 2013-12-20 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000233729 SCV001741349 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000233729 SCV001917965 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000233729 SCV001928079 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000233729 SCV001951783 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000233729 SCV001970279 likely benign not provided no assertion criteria provided clinical testing

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