ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3083C>T (p.Thr1028Ile)

dbSNP: rs397516002
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Total submissions: 7
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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 RCV000151077 SCV000198821 uncertain significance not specified 2015-08-07 criteria provided, single submitter clinical testing The p.Thr1028Ile variant in MYBPC3 has been identified in 4 individuals with HCM (Kapplinger 2014, LMM unpublished data) and was absent from large population st udies. Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. In summary, the clinical significance of the Thr1 028Ile variant is uncertain.
GeneDx RCV000766366 SCV000208147 uncertain significance not provided 2022-05-24 criteria provided, single submitter clinical testing Reported in patients referred for HCM genetic testing in the published literature (Kapplinger et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24510615, 26914223, 18403758)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001170189 SCV001332740 uncertain significance Cardiomyopathy 2022-03-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001170189 SCV001355385 uncertain significance Cardiomyopathy 2023-01-23 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 1028 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 26914223, 33495596, 33495597) as well as individuals with suspected hypertrophic cardiomyopathy (PMID: 24510615). This variant has been identified in 1/247100 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001214483 SCV001386166 uncertain significance Hypertrophic cardiomyopathy 2023-07-06 criteria provided, single submitter clinical testing 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 164050). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) or referred for HCM testing (PMID: 24510615, 26914223). This variant is present in population databases (rs397516002, gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1028 of the MYBPC3 protein (p.Thr1028Ile).
Ambry Genetics RCV002319445 SCV002608781 uncertain significance Cardiovascular phenotype 2023-04-18 criteria provided, single submitter clinical testing The p.T1028I variant (also known as c.3083C>T), located in coding exon 29 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3083. The threonine at codon 1028 is replaced by isoleucine, an amino acid with similar properties. This variant was observed in individuals reported to have hypertrophic cardiomyopathy (HCM); however, clinical details were limited (Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000627167 SCV000748031 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-02-14 flagged submission clinical testing

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