ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2807C>T (p.Thr936Met) (rs374946555)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158448 SCV000208383 uncertain significance not provided 2015-12-23 criteria provided, single submitter clinical testing This mutation is denoted p.Thr936Met (ACG>ATG): c.2807 C>T in exon 27 of the MYBPC3 gene (NM_000256.3). The T936M variant has not been published as a mutation or been reported as a benign polymorphism to our knowledge. The T936M variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T936M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Mutations in nearby residues (R943Q, R939W) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Nevertheless, the T936M variant has been reported as a variant of unknown significance in a 71 year old without clincal features of HCM (Bick A et al. 2012). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000537317 SCV000623576 uncertain significance Hypertrophic cardiomyopathy 2017-12-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 936 of the MYBPC3 protein (p.Thr936Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs374946555, ExAC 0.03%). This variant has been reported in individuals with dilated cardiomyopathy and in individuals in the general population (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 181130). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000619901 SCV000737382 uncertain significance Cardiovascular phenotype 2017-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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