ClinVar Genomic variation as it relates to human health

Identified in patients with DCM and early onset atrial fibrillation in published literature (Olson et al., 1998; Nguyen et al., 2021; Yoneda et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant results in significant reductions in maximal calcium regulated thin filament velocity (Debold et al., 2010); Published functional studies also demonstrate this variant, reported as R312H, results in decreased contractility and filament stability which authors predicted cause filament disarrays in intact cardiomyocytes (Hassoun et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R312H); This variant is associated with the following publications: (PMID: 22590617, 24736382, 31921954, 26061005, 9563954, 19799913, 34930662, 34495297, 34011823, 35457283)

ACMG codes: PS3, PP3, PP5

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 314 of the ACTC1 protein (p.Arg314His). This variant is present in population databases (rs121912673, gnomAD 0.003%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg314 amino acid residue in ACTC1. Other variant(s) that disrupt this residue have been observed in individuals with ACTC1-related conditions (PMID: 9563954, 23283745), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects ACTC1 function (PMID: 19799913, 22590617, 24736382). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACTC1 protein function. ClinVar contains an entry for this variant (Variation ID: 18323). This variant is also known as R312H. This missense change has been observed in individual(s) with clinical features of ACTC1-related conditions (PMID: 9563954, 34011823, 34495297, 34930662). It has also been observed to segregate with disease in related individuals.

This missense variant is located in the myosin head/motor domain of the ACTC1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental studies have shown that this variant may affect protein stability, calcium sensitivity and interaction with MYBPC3 (PMID: 19799913, 22590617, 24736382). However, clinical relevance of these observations is not known. This variant has been reported to segregate with dilated cardiomyopathy in three affected individuals from one family (PMID: 9563954). This variant was also identified in a 15-year-old unaffected relative in this family. Other DCM-associated genes were not tested in this study. This variant has been identified in 4/276578 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While there is a suspicion for a pathogenic role, available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as Variant of Uncertain Significance.