Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004813198 | SCV005438087 | pathogenic | Alpha-actinopathy | 2024-08-27 | reviewed by expert panel | curation | The NM_001100.4:c.124C>T variant in ACTA1 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 42 (legacy nomenclature: p.His40Tyr). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.72, which is above the threshold of 0.7, evidence that correlates with impact to ACTA1 function (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). In vitro studies demonstrated changes in actin localization and motility (PMID:15226407, 17227580, 27112274). In vivo studies in a mouse model demonstrated impaired function of ACTA1 and limited intrinsic force-generating capacity and maximal tetanic force (PMID:23613869, 23656990)(PS3). This variant has been reported in 4 probands/families with intranuclear rod and/or nemaline myopathies (PS4_Moderate; PMID:10508519, 12921789, 19562689). This variant has occured de novo with confirmed parental relationships in 1 individual and was reported to occur de novo with unconfirmed parental relationships in 1 individual with severe atypical nemaline myopathy with intranuclear nemaline bodies (PS2, PP4_Moderate; PMID:10508519, 19562689). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PS3, PS4_Moderate, PP4_Moderate, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024. |
| Labcorp Genetics |
RCV002000054 | SCV002229152 | pathogenic | Actin accumulation myopathy | 2022-08-15 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACTA1 function (PMID: 27112274). 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: 1452968). This variant is also known as p.His40Tyr. This missense change has been observed in individual(s) with autosomal dominant nemaline myopathy (PMID: 10508519). 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 histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 42 of the ACTA1 protein (p.His42Tyr). |
| OMIM | RCV003228037 | SCV003841096 | pathogenic | Congenital myopathy 2c, severe infantile, autosomal dominant | 1999-10-01 | no assertion criteria provided | literature only |