Submissions for variant NM_001100.4(ACTA1):c.676G>C (p.Glu226Gln)

dbSNP: rs1057521118

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000440063	SCV000521128	likely pathogenic	not provided	2016-10-05	criteria provided, single submitter	clinical testing	The E226Q variant was originally reported, using alternative nomenclature, as a heterozygous variant in a patient with severe nemaline myopathy (Sparrow et al., 2003). Subsequently, E226Q was observed in another patient with nemaline myopathy (Wallgren-Petterson et al., 2004); however, segregation analysis was not provided in either case. The E226Q variant was not observed in approximately 6,500 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 E226Q 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, and missense variants in nearby residues (L223P; E228Q; M229V/T/I) have been reported in the Human Gene Mutation Database in association with ACTA1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555238	SCV000638375	pathogenic	Actin accumulation myopathy	2022-07-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 226 of the ACTA1 protein (p.Glu226Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with nemaline myopathy (PMID: 12921789). This variant is also known as p.Glu224Gln. ClinVar contains an entry for this variant (Variation ID: 381640). 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. This variant disrupts the p.Glu226 amino acid residue in ACTA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12921789, 19562689). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.