ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3452C>T (p.Ala1151Val)

gnomAD frequency: 0.00004  dbSNP: rs779884363
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute RCV000999604 SCV001156307 uncertain significance Hypertrophic cardiomyopathy 2018-10-15 criteria provided, single submitter research MYBPC3 Ala1151Val has been reported in at least 1 HCM proband (Walsh R, et al., 2017) and is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a HCM proband with no family history of disease who also harbours a second MYBPC3 variant (c.821+1G>C). In silico tools PolyPhen2 and MutationTaster predict this variant to be deleterious, however SIFT predicts this variant to be 'tolerated'. As such we classify this as a variant of 'uncertain significance'.
Color Diagnostics, LLC DBA Color Health RCV001184393 SCV001350357 uncertain significance Cardiomyopathy 2023-05-12 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 1151 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33782553) and in individuals affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 9/235592 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 RCV002454250 SCV002617055 uncertain significance Cardiovascular phenotype 2019-05-30 criteria provided, single submitter clinical testing The p.A1151V variant (also known as c.3452C>T), located in coding exon 31 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3452. The alanine at codon 1151 is replaced by valine, an amino acid with similar properties. This variant has been reported in the Jackson Heart Study cohort and has been reported in a hypertrophic cardiomyopathy clinical genetic testing cohort; however, clinical details were limited in both studies (Bick AG et al. Am. J. Hum. Genet., 2012 Sep;91:513-9; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002505527 SCV002814070 uncertain significance Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2021-09-30 criteria provided, single submitter clinical testing
Invitae RCV000999604 SCV003016162 uncertain significance Hypertrophic cardiomyopathy 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1151 of the MYBPC3 protein (p.Ala1151Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27532257, 33782553). ClinVar contains an entry for this variant (Variation ID: 810763). 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.

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