Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000158275 | SCV000208210 | uncertain significance | not provided | 2017-06-29 | criteria provided, single submitter | clinical testing | p.Ala113Asp (GCC>GAC): c.338 C>A in exon 3 of the MYBPC3 gene (NM_000256.3). The Ala113Asp variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala113Asp results in a non-conservative amino acid substitution of a non-polar Alanine with a negatively charged Aspartic Acid at a position that is conserved in mammals. The Ala113Asp variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, control data from individuals of other ethnic backgrounds were not available to assess for a population-specific benign polymorphism. Only one nearby missense mutation (Pro102Leu) has been reported in association with hypertrophic cardiomyopathy (Kassem H et al., 2013). Additionally, in silico algorithms are not consistent in their predictions but at least two concur that Ala113Asp is benign to the protein structure/function. With the clinical and molecular information available at this time, we cannot definitively determine if Ala113Asp is a disease-causing mutation or a rare benign variant. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in DCM panel(s). |
| Color Diagnostics, |
RCV001178355 | SCV001342770 | uncertain significance | Cardiomyopathy | 2023-10-19 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with aspartic acid at codon 113 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 not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has not been identified 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. |