Submissions for variant NM_001613.4(ACTA2):c.592C>T (p.Arg198Cys)

gnomAD frequency: 0.00001  dbSNP: rs772862676

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001170401	SCV000319238	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-02-25	criteria provided, single submitter	clinical testing	The p.R198C variant (also known as c.592C>T), located in coding exon 5 of the ACTA2 gene, results from a C to T substitution at nucleotide position 592. The arginine at codon 198 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple subjects with aortic dissections or aneurysms (Regalado ES et al. Circ Cardiovasc Genet, 2015 Jun;8:457-64; Ambry internal data; GeneDx pers. comm.; Invitae pers. comm.). A likely pathogenic alteration affecting the same amino acid, p.R198H (c.593G>A), has also been reported in association with aortic disease (Regalado ES et al, Circ Cardiovasc Genet 2015 Jun; 8(3):457-64). 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	RCV000421033	SCV000516787	uncertain significance	not provided	2020-10-19	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance or likely pathological (ClinVar Variant ID# 263819; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25759435)
Invitae	RCV000692888	SCV000820736	pathogenic	Aortic aneurysm, familial thoracic 6	2024-01-05	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 198 of the ACTA2 protein (p.Arg198Cys). This variant is present in population databases (rs772862676, gnomAD 0.0009%). This missense change has been observed in individuals with thoracic aortic aneurysm and/or dissection (PMID: 25759435; Invitae). ClinVar contains an entry for this variant (Variation ID: 263819). 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.Arg198 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25759435; Invitae). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170401	SCV001332978	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-08-21	criteria provided, single submitter	clinical testing