Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000518896 | SCV000617033 | pathogenic | not provided | 2023-04-18 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); Has not been previously reported as pathogenic or benign to our knowledge |
| 3billion | RCV001809466 | SCV002059108 | likely pathogenic | Baraitser-winter syndrome 2 | 2022-01-03 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ACTG1 related disorder (ClinVar ID: VCV000449191, PS1_P). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000813525, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.802, 3CNET: 0.981, PP3_P). A missense variant is a common mechanism associated with Baraitser-Winter syndrome 2 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Invitae | RCV002527566 | SCV003345010 | uncertain significance | Autosomal dominant nonsyndromic hearing loss 20; Baraitser-winter syndrome 2 | 2023-11-27 | 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 210 of the ACTG1 protein (p.Arg210His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACTG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 449191). 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 ACTG1 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg210 amino acid residue in ACTG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30008475, 33584783). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |