ClinVar Miner

Submissions for variant NM_001100.3(ACTA1):c.172G>A (p.Asp58Asn) (rs1085308014)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Invitae RCV000794669 SCV000934090 likely pathogenic Nemaline myopathy 3 2018-10-10 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.

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