Submissions for variant NM_005159.5(ACTC1):c.1090T>A (p.Tyr364Asn)

dbSNP: rs1555418631

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000524029	SCV000621431	uncertain significance	not provided	2017-10-04	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ACTC1 gene. The Y364N variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The Y364N 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 in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae	RCV003766973	SCV004605603	uncertain significance	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2023-09-23	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 ACTC1 protein function. ClinVar contains an entry for this variant (Variation ID: 452611). This variant has not been reported in the literature in individuals affected with ACTC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 364 of the ACTC1 protein (p.Tyr364Asn).