ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3083C>T (p.Thr1028Ile) (rs397516002)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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clinical testing The p.Thr1028Ile variant in MYBPC3 has been identified in 4 individuals with HCM (Kapplinger 2014, LMM unpublished data) and was absent from large population st udies.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 2018-03-07 criteria provided, single submitter clinical testing The T1028I variant of uncertain significance in the MYBPC3 gene has been reported previously in three individuals with HCM, and was absent in 854 control alleles (Kapplinger et al., 2014). The T1028I variant was not observed in approximately 6,500 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 T1028I 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. In addition, this substitution occurs at a position that is conserved in mammals. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense variant in the same residue (T1028S) has been reported in association with HCM in a patient who also harbored a splice site variant on the other MYBPC3 allele (Morita et al., 2008). Additionally, variants in nearby residues (R1022C, R1022S, R1033W, R1033Q) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000627167 SCV000748031 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-02-14 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170189 SCV001332740 uncertain significance Cardiomyopathy 2018-08-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV001170189 SCV001355385 uncertain significance Cardiomyopathy 2019-08-21 criteria provided, single submitter clinical testing
Invitae RCV001214483 SCV001386166 uncertain significance Hypertrophic cardiomyopathy 2019-08-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1028 of the MYBPC3 protein (p.Thr1028Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) or referred for HCM testing (PMID: 24510615, 26914223). ClinVar contains an entry for this variant (Variation ID: 164050). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). 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. 5

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