ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2056G>C (p.Ala686Pro)

gnomAD frequency: 0.00004  dbSNP: rs367992212
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000699147 SCV000827845 uncertain significance Hypertrophic cardiomyopathy 2023-10-03 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 686 of the MYBPC3 protein (p.Ala686Pro). This variant is present in population databases (rs367992212, gnomAD 0.004%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 33782553). ClinVar contains an entry for this variant (Variation ID: 576612). 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 RCV001181817 SCV001347052 uncertain significance Cardiomyopathy 2023-05-05 criteria provided, single submitter clinical testing This missense variant replaces alanine with proline at codon 686 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 an individual affected with hypertrophic cardiomyopathy (PMID: 30297972, 33782553). This variant has been identified in 2/264986 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.
Ambry Genetics RCV002422552 SCV002725563 uncertain significance Cardiovascular phenotype 2022-06-29 criteria provided, single submitter clinical testing The p.A686P variant (also known as c.2056G>C), located in coding exon 21 of the MYBPC3 gene, results from a G to C substitution at nucleotide position 2056. The alanine at codon 686 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Ho CY et al. Circulation, 2018 10;138:1387-1398). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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