Submissions for variant NM_001100.4(ACTA1):c.236C>T (p.Thr79Ile)

dbSNP: rs1659978452

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001211040	SCV001382561	pathogenic	Actin accumulation myopathy	2022-03-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr79 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been observed in individuals with ACTA1-related conditions (PMID: 12921789), which suggests that this may be a clinically significant amino acid residue. 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: 941283). This missense change has been observed in individual(s) with clinical features of nemaline 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 threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 79 of the ACTA1 protein (p.Thr79Ile).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001211040	SCV003761243	likely pathogenic	Actin accumulation myopathy	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Thr79Ile variant in ACTA1 was identified by our study in one individual with nemaline myopathy. Trio exome analysis showed this variant to be de novo. The p.Thr79Ile variant in ACTA1 has not been previously reported in the literature in individuals with nemaline myopathy 3. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Thr79Ala, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 31218456, PMID: 15236405, PMID: 12921789). This variant has been reported in ClinVar and has been interpreted as pathogenic by Invitae (Variation ID: 941283). This variant was absent from large population studies. The number of missense variants reported in ACTA1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant nemaline myopathy 3. ACMG/AMP Criteria applied: PS2_Moderate, PM2_Supporting, PM5_Supporting, PP2, PP3 (Richards 2015).