Submissions for variant NM_001100.4(ACTA1):c.172G>A (p.Asp58Asn)

dbSNP: rs1085308014

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	RCV004992269	SCV005442795	likely pathogenic	Alpha-actinopathy	2024-08-27	reviewed by expert panel	curation	The c.172G>A variant in ACTA 1 is a missense variant predicted to cause a substitution of aspartic acid by asparagine at amino acid position 58. This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.893, which is above the threshold of 0.7 set by the CM VCEP (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). This variant was observed to occur de novo in a proband with congenital hypotonia, muscle weakness, failure to thrive, poor feeding, developmental delay and normal creatine kinase levels (PS2, SCV000934090.3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PM2_Supporting, PP2, PP3 (Congenital Myopathies VCEP specifications version 2; 08/27/2024).
GeneDx	RCV000489996	SCV000577830	likely pathogenic	not provided	2015-04-18	criteria provided, single submitter	clinical testing	The D58N variant in the ACTA1 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The D58N variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D58N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (G48C, G48D, M49V, G50C, G57R, I66N, I66S, T68I) have been reported in the Human Gene Mutation Database in association with ACTA1-related myopathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. The D58N variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000794669	SCV000934090	likely pathogenic	Actin accumulation myopathy	2018-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 58 of the ACTA1 protein (p.Asp58Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with congenital myopathy (Invitae). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 427190). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.