ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1565C>T (p.Ala522Val) (rs370362589)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000244716 SCV000320243 uncertain significance Cardiovascular phenotype 2015-09-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (benign),Insufficient or conflicting evidence
GeneDx RCV000439878 SCV000520092 uncertain significance not specified 2017-02-21 criteria provided, single submitter clinical testing The A522V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A522V variant was not observed with any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense variants in nearby residues (G523W, G523R, Y525S, G531R) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, a missense variant affecting the same residue (A522T) has been classified as a likely benign variant by GeneDx and other laboratories in the ClinVar database (Landrum et al., 2014). Additionally, the A522V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000460349 SCV000546410 uncertain significance Hypertrophic cardiomyopathy 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 522 of the MYBPC3 protein (p.Ala522Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs370362589, ExAC 0.02%). This variant has not been reported in the literature in individuals with MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 264356). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000439878 SCV000710915 uncertain significance not specified 2016-04-14 criteria provided, single submitter clinical testing The p.Ala522Val variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy, but has been identified in 2/9788 African chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs 370362589). Alanine (Ala) at position 522 is poorly conserved in evolution and t he change to valine (Val) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimat ed to be correct 89% of the time (Jordan 2011). In summary, the clinical signifi cance of the p.Ala522Val variant is uncertain.

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