Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000150128 | SCV000196979 | uncertain significance | not specified | 2019-06-28 | criteria provided, single submitter | clinical testing | The p.Ile252Met variant in ACTC1 has been identified in 1 individual with DCM (LMM data) and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong evidence for or against an impact to the protien. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2. |
| Genetics and Molecular Pathology, |
RCV003447503 | SCV004175310 | uncertain significance | Primary dilated cardiomyopathy | 2023-07-05 | criteria provided, single submitter | clinical testing | The ACTC1 c.756T>G variant is classified as VUS (PM2, PS4_Supporting, PP2, PP3) The ACTC1 c.756T>G variant is a single nucleotide change in exon 5/7 of the ACTC1 gene, which is predicted to change the amino acid isoleucine at position 252 in the protein, to methionine. The variant has been reported in at least 3 probands with a clinical presentation of Dilated Cardiomyopathy (PMID#22464770 and ClinVar)(PS4_Supporting) and is absent from population databases (PM2). This is a missense variant in a constrained gene where missense variants are a common mechanism of disease and benign variation is rare (PP2). A different change to the same amino acid (p.Ile252Thr) has also been reported in individuals with DCM. This variant is in a region of the gene highly intolerant to change and computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs371940910), is reported as disease causing in the HGMD database (CM22827) and reported as uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 162706). |
| Invitae | RCV003764902 | SCV004568829 | uncertain significance | Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 | 2022-11-20 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Ile252 amino acid residue in ACTC1. Other variant(s) that disrupt this residue have been observed in individuals with ACTC1-related conditions (PMID: 28416588; Invitae), which suggests that this may be a clinically significant amino acid residue. 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 not expected to disrupt ACTC1 protein function. ClinVar contains an entry for this variant (Variation ID: 162706). This missense change has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 22464770; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 252 of the ACTC1 protein (p.Ile252Met). |