Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004813113 | SCV005438090 | likely pathogenic | Alpha-actinopathy | 2024-08-27 | reviewed by expert panel | curation | The variant NM_001100.3:c.1054T>C in ACTA1 is a missense variant predicted to cause substitution of serine by proline at amino acid 352 (p.Ser352Pro). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.942, which is above the threshold necessary to apply PP3. ACTA1, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). There is no published data on this variant, however Invitae has reported the variant in three unrelated probands, two of which presented with hypotonia (PS4_Supporting; SCV000638354.5). In addition, one of these probands had a de novo occurrence of the variant with parental relationships unconfirmed (PM6). In summary, the variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: PM2_Supporting, PP2, PP3, PS4_Supporting, PM6 (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024). |
| Labcorp Genetics |
RCV000543487 | SCV000638354 | pathogenic | Actin accumulation myopathy | 2022-06-13 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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 ACTA1 protein function. ClinVar contains an entry for this variant (Variation ID: 464113). This missense change has been observed in individual(s) with congenital myopathy (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 352 of the ACTA1 protein (p.Ser352Pro). |