ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1976T>C (p.Ile659Thr) (rs397515941)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035458 SCV000059106 uncertain significance not specified 2012-07-11 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Ile659Thr v ariant in MYBPC3 has not been reported in the literature nor been detected in la rge and broad populations (European and African American) screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). This low frequency is consistent with a disease causing role but insufficient to establish this wit h confidence. Our laboratory has identified this variant 1 infant with DCM. Comp utational analyses (biochemical amino acid properties, conservation, AlignGVGD, and SIFT) suggest that this variant may impact the protein, though this informat ion is not predictive enough to determine pathogenicity. Additional studies are needed to fully assess its clinical significance.
Ambry Genetics RCV000252578 SCV000319097 uncertain significance Cardiovascular phenotype 2013-09-19 criteria provided, single submitter clinical testing
Invitae RCV000814323 SCV000954727 uncertain significance Hypertrophic cardiomyopathy 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 659 of the MYBPC3 protein (p.Ile659Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257). ClinVar contains an entry for this variant (Variation ID: 42590). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000035458 SCV000280229 uncertain significance not specified 2011-03-10 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. MYBPC3 p.Ile659Thr This variant is novel. This variant results in isoleucine at codon 659 replaced by threonine, an amino acid with a few similar properties. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation taster predicts this variant to be disease-causing. The isoleucine at codon 659 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon or at nearby codons. In total the variant has not been seen in ~6,500 individuals from publicly available population datasets. There is no variation at codon 659 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/20/13). Note that this dataset does not match the patient's ancestry (Mexico/N. American). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 9/20/13).

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