ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.2890G>T (p.Ala964Ser) (rs144907522)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618195 SCV000736625 likely benign Cardiovascular phenotype 2018-02-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000037463 SCV000051406 benign not specified 2013-06-24 criteria provided, single submitter research
GeneDx RCV000037463 SCV000715074 likely benign not specified 2017-08-11 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.
Integrated Genetics/Laboratory Corporation of America RCV000037463 SCV000919832 likely benign not specified 2018-11-05 criteria provided, single submitter clinical testing Variant summary: MYH6 c.2890G>T (p.Ala964Ser) results in a conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 277246 control chromosomes, predominantly at a frequency of 0.005 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 200 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 African origin. c.2890G>T has been reported in the literature in individuals affected with hypoplastic left heart syndrome (Tomita-Mitchell_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000461438 SCV000557925 benign Familial hypertrophic cardiomyopathy 14 2017-12-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037463 SCV000061121 likely benign not specified 2015-11-09 criteria provided, single submitter clinical testing p.Ala964Ser in exon 22 of MYH6: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (51/10406) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs144907522).

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