ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3415G>A (p.Val1139Ile) (rs373519667)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035588 SCV000059239 uncertain significance not specified 2012-02-07 criteria provided, single submitter clinical testing The Val1139Ile variant (MYBPC3) has been identified in 1/3308 of African America n chromosomes by the NHLBI Exome Sequencing Project in a broad population (http: // Valine (Val) at position 1139 is highly conserved in mammals and across evolutionarily distant species, though computational analy ses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not p rovide strong support for or against an impact to the protein. Additional inform ation is needed to fully assess the clinical significance of the Val1138Ile vari ant.
GeneDx RCV000766374 SCV000208172 uncertain significance not provided 2018-08-31 criteria provided, single submitter clinical testing The V1139I variant of uncertain significance in the MYBPC3 gene has been reported in association with HCM, although specific clinical information was not provided (Walsh et al., 2017). This variant has also been observed in other unrelated individuals referred for DCM genetic testing at GeneDx. However, one of these individuals also harbored pathogenic and likely pathogenic variants in other cardiac genes that likely explained their disease. The V1139I variant is observed in 10/22,592 alleles from individuals of African ancestry and 8/28,974 alleles from individuals of South Asian ancestry in large population cohorts (Lek et al., 2016). The V1139I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Illumina Clinical Services Laboratory,Illumina RCV000266983 SCV000372285 uncertain significance Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000324482 SCV000372286 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000381126 SCV000372287 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000324482 SCV000749764 uncertain significance Hypertrophic cardiomyopathy 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1139 of the MYBPC3 protein (p.Val1139Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs373519667, ExAC 0.05%). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42713). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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