ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1471G>A (p.Val491Met) (rs730880543)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158092 SCV000208027 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing The V491M variant of uncertain significance in the MYBPC3 gene has been reported in association with HCM (Coppini et al., 2014; Lopes et al., 2015; Walsh et al., 2017). This variant has been identified in at least two unrelated individuals referred for HCM genetic testing at GeneDx. The V491M variant is observed in 12/111,626 (0.1%) of alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). V491M 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. Nevertheless, other pathogenic or likely pathogenic variants at a nearby residue (R495G, R495W, R495Q) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Ambry Genetics RCV000245534 SCV000318274 uncertain significance Cardiovascular phenotype 2017-05-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000454557 SCV000539827 uncertain significance not specified 2016-12-02 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 1 patient with HCM. It is present in gnomAD at a Max MAF of 0.01% (12 European alleles). It is classified in ClinVar with 1 star as Likely Pathogenic by GeneDx (although their blurb suggests VUS) and VUS by Ambry. The variant is not present in Sarcomere Polyphen.
Invitae RCV000467731 SCV000546451 uncertain significance Hypertrophic cardiomyopathy 2016-04-21 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 491 of the MYBPC3 protein (p.Val491Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs730880543, ExAC <0.01%). This variant has been reported in the literature in two unrelated individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 25524337, 20800588). ClinVar contains an entry for this variant (Variation ID: 180940). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000777606 SCV000913473 uncertain significance Cardiomyopathy 2018-10-03 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the C3 Ig-like domain of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 25524337, 20800588). This variant has also been identified in 14/246122 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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