ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.4136C>T (p.Thr1379Met) (rs145611185)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 Familial hypertrophic cardiomyopathy 14 2020-11-27 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 uncertain significance Familial hypertrophic cardiomyopathy 14 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000233729 SCV001149134 uncertain significance not provided 2017-03-01 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.
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

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