Submissions for variant NM_001613.4(ACTA2):c.766C>T (p.Arg256Cys)

dbSNP: rs886038852

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV003243034	SCV000318548	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-08-06	criteria provided, single submitter	clinical testing	The p.R256C variant (also known as c.766C>T), located in coding exon 6 of the ACTA2 gene, results from a C to T substitution at nucleotide position 766. The arginine at codon 256 is replaced by cysteine, an amino acid with highly dissimilar properties. Based on internal structural analysis, this alteration is deleterious to the local structure (Ambry internal data). Additionally, this alteration has been reported in individuals with thoracic aortic aneurysm and dissection (TAAD) and segregated with disease in two families (Ambry internal data; external communication). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV001577769	SCV001805215	uncertain significance	not provided	2023-12-04	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859445	SCV002257256	likely pathogenic	Aortic aneurysm, familial thoracic 6	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 256 of the ACTA2 protein (p.Arg256Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with aortic aneurysm and/or aortic dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 263578). 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 not expected to disrupt ACTA2 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg256 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29543232; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Fulgent Genetics, Fulgent Genetics	RCV005044510	SCV005678980	likely pathogenic	Aortic aneurysm, familial thoracic 6; Multisystemic smooth muscle dysfunction syndrome; Moyamoya disease 5	2023-12-29	criteria provided, single submitter	clinical testing