ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3137C>T (p.Thr1046Met) (rs371061770)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766369 SCV000208152 uncertain significance not provided 2015-04-16 criteria provided, single submitter clinical testing This variant is denoted p.Thr1046Met (ACG>ATG): c.3137 C>T in exon 29 of the MYBPC3 gene (NM_000256.3). The T1046M variant has has been reported in three unrelated patients with HCM in the literature, all over the age of 50 (Anan et al., 2007; Bahrudin et al., 2008; Inamori et al., 2012). One of these patients also had inclusion body myositis; it was unclear whether the HCM was related to the inclusion body myositis or was incidental (Inamori et al., 2012). The T1046M variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The T1046M 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. However, this substitution occurs at a position that is not conserved across species. In addition, in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, no missense mutations in neighboring residues have been reported in association with cardiomyopathy, indicating this region of the protein may be tolerant of change. 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 DCM-CRDM panel(s).
Invitae RCV001084743 SCV000218988 likely benign Hypertrophic cardiomyopathy 2019-12-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000158217 SCV000270427 likely benign not specified 2014-12-16 criteria provided, single submitter clinical testing p.Thr1046Met variant in exon 29 of MYBPC3: This variant is not expected to have clinical significance because the threonine (Thr) at position 1046 is not conser ved in mammals or evolutionarily distant species. Of note, 5 mammals (macaque, cat, dog, panda, and cape golden mole) have a methionine (Met) at this position despite high nearby amino acid conservation. Moreover, this variant was predicte d to be benign using a computational tool clinically validated by our laboratory . This tool's benign prediction is estimated to be correct 89% of the time (Jord an 2011).
Color RCV000777870 SCV000913877 uncertain significance Cardiomyopathy 2019-11-19 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148658 SCV000190377 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research

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