ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1147C>G (p.Leu383Val)

gnomAD frequency: 0.00001  dbSNP: rs11570077
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158334 SCV000208269 likely pathogenic not provided 2013-10-21 criteria provided, single submitter clinical testing The Leu383Val variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Leu383Val results in a conservative amino acid substitution of one non-polar amino acid with another, it occurs at a residue that is conserved across species. In silico analysis predicts Leu383Val is damaging to the protein structure/function. Mutations in nearby residues (Pro371Arg, His379Pro, Val385Met) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the Leu383Val variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, while Leu383Val is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in HCM panel(s).
Mendelics RCV000988546 SCV001138308 uncertain significance Hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001227943 SCV001400323 uncertain significance Hypertrophic cardiomyopathy 2023-07-22 criteria provided, single submitter clinical testing This variant is present in population databases (rs11570077, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 383 of the MYBPC3 protein (p.Leu383Val). This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 21520333). 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. 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. ClinVar contains an entry for this variant (Variation ID: 181062).
Ambry Genetics RCV002453543 SCV002613575 likely benign Cardiovascular phenotype 2021-06-15 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health RCV001227943 SCV004834668 uncertain significance Hypertrophic cardiomyopathy 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces leucine with valine at codon 383 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 an individual affected with hypertrophic cardiomyopathy (PMID: 32841044). This variant has been identified in 19/246460 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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