Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Juno Genomics, |
RCV000019988 | SCV006079948 | likely pathogenic | Dilated cardiomyopathy 1R | criteria provided, single submitter | clinical testing | PM2_Supporting+PP3_Strong+PP1 | |
| Color Diagnostics, |
RCV005402803 | SCV006064431 | uncertain significance | Cardiomyopathy | 2023-02-02 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with histidine at codon 314 of the ACTC1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant adversely affects protein stability, calcium sensitivity, interaction with MYBPC3, and downstream SRF signaling (PMID: 19799913, 22590617, 24736382, 31921954). To our knowledge, this variant has not been reported in individuals affected with hypertrophic cardiomyopathy but has been observed in individuals affected with dilated cardiomyopathy (PMID: 9563954, 34011823; ClinVar SCV000577700.5). This variant has been identified in 4/282300 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in hypertrophic cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| All of Us Research Program, |
RCV003996110 | SCV004844810 | uncertain significance | Hypertrophic cardiomyopathy | 2024-04-08 | criteria provided, single submitter | clinical testing | 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. |
| Ai |
RCV000489472 | SCV002502926 | likely pathogenic | not provided | 2022-03-25 | criteria provided, single submitter | clinical testing | |
| Hudson |
RCV000019988 | SCV000891768 | likely pathogenic | Dilated cardiomyopathy 1R | 2018-08-24 | criteria provided, single submitter | research | ACMG codes: PS3, PP3, PP5 |
| Labcorp Genetics |
RCV000648300 | SCV000770114 | likely pathogenic | Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 | 2024-06-19 | criteria provided, single submitter | clinical testing | 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%). 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 variant is also known as R312H. ClinVar contains an entry for this variant (Variation ID: 18323). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ACTC1 function (PMID: 19799913, 22590617, 24736382, 35457283). 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. 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. |
| Gene |
RCV000489472 | SCV000577700 | likely pathogenic | not provided | 2024-01-31 | criteria provided, single submitter | clinical testing | Identified in patients with DCM, HCM, and early onset atrial fibrillation in published literature (PMID: 34011823, 9563954, 34495297); 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 (PMID: 19799913); Published functional studies also demonstrate this variant results in decreased contractility and filament stability which authors predicted cause filament disarrays in intact cardiomyocytes (PMID: 35457283); 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, 34930662, 34495297, 35457283, 34011823, 9563954, 36264615, 35130036, 19799913) |
| KTest Genetics, |
RCV000019988 | SCV001499950 | likely pathogenic | Dilated cardiomyopathy 1R | no assertion criteria provided | clinical testing | ||
| OMIM | RCV000019988 | SCV000040286 | pathogenic | Dilated cardiomyopathy 1R | 1998-05-01 | no assertion criteria provided | literature only |