ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1294G>A (p.Ala432Thr)

gnomAD frequency: 0.00004  dbSNP: rs371167525
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Total submissions: 3
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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 RCV000035386 SCV000059034 uncertain significance not specified 2012-08-24 criteria provided, single submitter clinical testing The Ala432Thr variant in MYBPC3 has not been reported in the literature but has been identified by our laboratory in one individual with neonatal HCM, who also carried two other variants of uncertain significance. This variant has been dete cted in 1/8500 European American chromosomes from a broad population screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Note th at this could represent a presymptomatic individual. Computational analyses (bio chemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) su ggest that the Ala432Thr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, additional stu dies are needed to fully assess its clinical significance.
Invitae RCV000556207 SCV000623522 uncertain significance Hypertrophic cardiomyopathy 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 432 of the MYBPC3 protein (p.Ala432Thr). This variant is present in population databases (rs371167525, gnomAD 0.007%). This missense change has been observed in individuals with dilated cardiomyopathy, hypertrophic cardiomyopathy, and/or MYBPC3-related conditions (PMID: 27532257, 33782553, 34935411; Invitae). ClinVar contains an entry for this variant (Variation ID: 42520). 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. 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.
Color Diagnostics, LLC DBA Color Health RCV003531909 SCV004358734 uncertain significance Cardiomyopathy 2023-10-23 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 432 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257, 33782553). This variant was also reported in one individual who was affected with dilated cardiomyopathy (PMID: 34935411). This variant has been identified in 6/244146 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.

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