Submissions for variant NM_001613.4(ACTA2):c.635G>A (p.Arg212Gln)

dbSNP: rs397516685

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000181024	SCV000060855	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-08-18	criteria provided, single submitter	clinical testing	The p.Arg212Gln variant in ACTA2 has been reported in at least 4 individuals (1 de novo, paternity confirmed) with familial thoracic aortic aneurysm disease (TAAD) and segregated with TAAD in 6 affected individuals from 1 family as well as with 1 sister with premature stroke and 1 mother with CAD from another family (Guo 2009 PMID: 19409525, Morisaki 2009 PMID: 19639654, Fang 2017 PMID: 28855619). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial TAAD. ACMG/AMP Criteria applied: PS2, PP1_Strong, PM2, PP3, PS4_Supporting.
GeneDx	RCV000211887	SCV000233299	pathogenic	not provided	2021-01-07	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 44219; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21248741, 25759435, 25910212, 19409525, 19639654, 28855619, 24793577, 29687370, 30990720)
Invitae	RCV000551317	SCV000646318	pathogenic	Aortic aneurysm, familial thoracic 6	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 212 of the ACTA2 protein (p.Arg212Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thoracic aortic disease (PMID: 19409525, 19639654). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44219). 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%. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000778290	SCV000914468	pathogenic	ACTA2-Related Disorders	2018-10-22	criteria provided, single submitter	clinical testing	The ACTA2 c.635G>A (p.Arg212Gln) missense variant has been reported in at least five studies in which it is found in at least seven individuals including in a heterozygous state in at least four individuals with thoracic aortic aneurysms and aortic dissections, two with annuloaortic ectasia, and one with Moyamoya disease (Guo et al. 2009; Morisaki et al. 2009; Regalado et al. 2015; Fang et al. 2017; Volozonoka et al. 2018). The p.Arg212Gln variant was shown to segregate with disease in three different families including one family where the p.Arg212Gln variant was observed de novo (paternity confirmed) and two other families where the p.Arg212Gln was detected in four other affected family members and absent in five healthy family members over at least two generations (Guo et al. 2009; Morisaki et al. 2009). The p.Arg212Gln variant was absent from 382 controls and is not found in the 1000 Genomes project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database, in a region with good sequence coverage, and hence is presumed to be rare. Based on the collective evidence, the p.Arg212Gln variant is classified as pathogenic for ACTA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181024	SCV000918388	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-10-24	criteria provided, single submitter	clinical testing	Variant summary: ACTA2 c.635G>A (p.Arg212Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250572 control chromosomes (gnomAD). c.635G>A has been reported in the literature in multiple individuals affected with Thoracic Aortic Aneurysms and Dissections, premature stroke, and CAD (Morisaki_2009, Guo_2009, Fang_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions (evaluation after 2014) cites the variant once as likely pathogenic and three times as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics	RCV000211887	SCV000927532	likely pathogenic	not provided	2018-02-15	criteria provided, single submitter	clinical testing
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374803	SCV001439504	likely pathogenic	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Ambry Genetics	RCV000181024	SCV002658034	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2016-12-30	criteria provided, single submitter	clinical testing	The p.R212Q pathogenic mutation (also known as c.635G>A), located in coding exon 6 of the ACTA2 gene, results from a G to A substitution at nucleotide position 635. The arginine at codon 212 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been described in families with thoracic aortic aneurysms and dissections (TAAD), co-segregating with disease in multiple relatives (Morisaki H et al. Hum Mutat. 2009;30:1406-11). In one study, this alteration was confirmed to be a de novo occurrence in a patient with premature stroke prior to presenting with acute aortic dissection (Guo DC et al. Am J Hum Genet. 2009;84:617-27). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000551317	SCV004239260	pathogenic	Aortic aneurysm, familial thoracic 6	2023-09-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944904	SCV004760996	pathogenic	ACTA2-related condition	2024-01-03	criteria provided, single submitter	clinical testing	The ACTA2 c.635G>A variant is predicted to result in the amino acid substitution p.Arg212Gln. This variant has been reported to segregate with disease in families with thoracic aortic aneurysm and dissection or related conditions (Guo et al. 2009. PubMed ID: 19409525; Morisaki et al. 2009. PubMed ID: 19639654; Regalado et al. 2015. PubMed ID: 25759435). In one individual, this variant was reported to occur de novo (Guo et al. 2009. PubMed ID: 19409525). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic.
Genomics England Pilot Project, Genomics England	RCV000551317	SCV001760261	pathogenic	Aortic aneurysm, familial thoracic 6		no assertion criteria provided	clinical testing