ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2728C>A (p.Pro910Thr) (rs397515985)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172008 SCV000050982 uncertain significance Primary familial hypertrophic cardiomyopathy 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035525 SCV000059175 uncertain significance not specified 2017-01-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000035525 SCV000208103 uncertain significance not specified 2017-01-18 criteria provided, single submitter clinical testing The P910T variant of uncertain significance in the MYBPC3 gene has been reported previously in association with cardiomyopathy (Olivotto et al., 2008; Hershberger et al., 2010; Waldmüller et al., 2011). The P910T variant was initially identified in one individual with hypertrophic cardiomyopathy (HCM) who also harbored another variant in the MYBPC3 gene (Olivotto et al., 2008). Subsequently, P910T was identified in one proband with dilated cardiomyopathy (DCM) who also harbored a variant in the TNNC1 gene (Hershberger et al., 2010). A relative of this proband harbored only P910T in MYBPC3 and had a normal ECG and echocardiogram at age 38 years, and another relative harbored the familial variant in the TNNC1 gene and had no evidence of cardiomyopathy at age 63 years (Pinto et al., 2011). In addition, Waldmüller et al. (2011) identified P910T in an additional unrelated patient with HCM and Brion et al. (2012) reported P910T in one case of sudden infant death syndrome (SIDS). The P910T 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. Nevertheless, this substitution occurs at a position that is not conserved and in silico analysis predicts this variant likely does not alter the protein structure/function. Additionally, the P910T variant has been observed in 0.1% of alleles from individuals of European ancestry in large population cohorts, indicating it may be a rare benign variant (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000557150 SCV000623569 uncertain significance Hypertrophic cardiomyopathy 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 910 of the MYBPC3 protein (p.Pro910Thr). The proline residue is weakly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs397515985, ExAC 0.09%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 21835320, 26914223, 25351510), dilated cardiomyopathy (PMID: 20215591), and in individuals who died unexpectedly (PMID: 22361390, 21499742). However, in one of the individuals with hypertrophic cardiomyopathy, a pathogenic allele was also identified in MYBPC3 which suggests that this c.2728C>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 42656). 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 tolerated, 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 RCV000617870 SCV000735984 uncertain significance Cardiovascular phenotype 2016-11-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000771802 SCV000904499 uncertain significance Cardiomyopathy 2018-07-03 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the fibronectin type 3 domain C7 of the MYBPC3 gene. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Proline at this position is poorly conserved and different amino acids are tolerated in many mammalian species, although variant threonine is not observed. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 21835320, 24111713, 26914223), dilated cardiomyopathy (PMID: 20215591) and sudden infant death syndrome (PMID: 22361390). One individual with hypertrophic cardiomyopathy had a different pathogenic variant in the same gene (PMID: 21835320), suggesting that this variant may not be a disease-causing variant. This variant has been identified in 25/168726 chromosomes (24/69342 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Mendelics RCV000988538 SCV001138293 uncertain significance Familial hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157314 SCV000207049 uncertain significance Brugada syndrome 2014-08-01 no assertion criteria provided clinical testing

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