ClinVar Genomic variation as it relates to human health

The p.Val671Ile variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy or in large population studies. Computational prediction t ools and conservation analysis suggest that the p.Val671Ile variant may impact t he protein, though this information is not predictive enough to determine pathog enicity. In summary, the clinical significance of the p.Val671Ile variant is unc ertain.

This sequence change replaces valine with isoleucine at codon 671 of the MYBPC3 protein (p.Val671Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28356264). ClinVar contains an entry for this variant (Variation ID: 228865). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.

The MYBPC3 c.2011G>A variant is predicted to result in the amino acid substitution p.Val671Ile. This variant was reported in an individual with dilated cardiomyopathy (Marschall et al. 2019. PubMed ID: 31737537). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47361258-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This missense variant replaces valine with isoleucine at codon 671 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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: 28356264, 30696458). This variant has been identified in 1/248852 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.

This missense variant replaces valine with isoleucine at codon 671 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 individuals affected with hypertrophic cardiomyopathy (PMID: 28356264, 30696458). This variant has also been identified in 1/248852 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

The p.V671I variant (also known as c.2011G>A), located in coding exon 21 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2011. The valine at codon 671 is replaced by isoleucine, an amino acid with highly similar properties. This variant was reported in a hypertrophic cardiomyopathy (HCM) cohort, detected in one individual who also had an MYL2 variant; however, clinical details were limited (G&oacute;mez J et al. Circ Cardiovasc Genet, 2017 Apr;10). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val671Ile (c.2011G>A) in the MYBPC3 gene. Given that the variant is novel and there is no data connecting it to disease, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant is novel. Sequencing of individuals from the general population has shown that 4-8% of all individuals have a rare or novel variant in one of the HCM genes included in this test (Pan et al 2012). Thus when we find a novel variant in an HCM gene it could either be a causative variant or one of the many benign unique variants we all have. The majority of pathogenic variants in MYBPC3 are nonsense, frameshift, or splicing. Thus when a missense variant is seen very strong evidence is needed to link it to disease. There is no variation at codon 671 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 8th, 2015).