rs772862676
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_001613.4(ACTA2):c.592C>T(p.Arg198Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R198H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001613.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTA2 | NM_001613.4 | c.592C>T | p.Arg198Cys | missense_variant | 6/9 | ENST00000224784.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTA2 | ENST00000224784.10 | c.592C>T | p.Arg198Cys | missense_variant | 6/9 | 1 | NM_001613.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250946Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135614
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461660Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727138
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 25, 2020 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 21, 2020 | - - |
Aortic aneurysm, familial thoracic 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 19, 2020 | 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) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at