Submissions for variant NM_001613.4(ACTA2):c.116G>A (p.Arg39His)

dbSNP: rs794728021

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181015	SCV000233289	likely pathogenic	not provided	2022-06-09	criteria provided, single submitter	clinical testing	Has been reported in association with aortic dissection or aortopathy (Regalado et al., 2014; Yang et al., 2016); 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; This variant is associated with the following publications: (PMID: 19409525, 21248741, 27611364, 26934405, 24243736, 26153420, 20689142, 29907982, 21937134, 21212136)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533011	SCV000646311	pathogenic	Aortic aneurysm, familial thoracic 6	2024-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 39 of the ACTA2 protein (p.Arg39His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with aortic dissections (PMID: 19409525, 27611364; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199666). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.Arg39 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21248741, 21733706, 21937134, 24243736, 25644172, 25759435). 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.
Ambry Genetics	RCV000770644	SCV000738463	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-05-15	criteria provided, single submitter	clinical testing	The p.R39H variant (also known as c.116G>A), located in coding exon 1 of the ACTA2 gene, results from a G to A substitution at nucleotide position 116. The arginine at codon 39 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in multiple unrelated individuals with ACTA2-related vascular phenotypes (Guo DC et al, Am. J. Hum. Genet. 2009 May; 84(5):617-27; Regalado ES et al, Am. J. Med. Genet. A 2014 Jan; 164A(1):106-12; Yang H et al. Sci Rep, 2016 09;6:33002; Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192; GeneDx pers. comm.; Invitae pers. comm.). This variant was not reported in population-based 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770644	SCV000902098	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2016-10-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779683	SCV000916411	likely pathogenic	Familial aortopathy	2018-09-24	criteria provided, single submitter	clinical testing	Variant summary: ACTA2 c.116G>A (p.Arg39His) results in a non-conservative amino acid change affecting a highly conserved residue located in the subdomain 2 (SD2) of the encoded protein sequence, whose dynamics are essential for ATP hydrolysis (Guo 2009). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 121750 control chromosomes (ExAC and publication data). The variant has been reported in two unrelated families with multiple affected family members who had TAAD, Type A or Type B aortic dissection, coronary artery disease, patent ductus arteriosus, and/or stroke (Guo 2009), however, only ACTA2 was screened for in these families, and one unaffected individual, above the average age of onset for aortopathy (20 y/o), from each family was identified as a carrier of R39H. After contacting the corresponding author for this paper, they indicated that there has been no addtional follow-up with the discordant members from the two families carrying the variant of interest since the publication. The variant was also reported recently in a patient with aortic dissection, and in his father with aortic aneurism (Overwater 2018). In addition, the variant was identified in an internal specimen (18 month old female whose phenotype is unknown), whose mother was indicated to be a carrier of the variant of interest and presented with stroke, left MCA infarcts, history of hyperplastic vascular myopathy and aneurysms. A missense variant at the same position, R39C, was reported in patients with aortic aneurysm or mild aortic dilatation and insufficiency, indicating that R39 is a critical amino acid and changes at this position could affect function of ACTA2 (Hoffjan 2011). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (classifying the variant as Pathogenic, Likely pathogenic or VUS). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Blueprint Genetics	RCV000181015	SCV000927802	pathogenic	not provided	2018-07-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000533011	SCV004242458	pathogenic	Aortic aneurysm, familial thoracic 6	2023-12-13	criteria provided, single submitter	clinical testing	Criteria applied: PM5_STR,PS4_MOD,PM2,PP2,PP3
Molecular Genetics, Royal Melbourne Hospital	RCV000770644	SCV004812292	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change in ACTA2 is predicted to replace arginine with histidine at codon 39, p.(Arg39His). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the SD2 domain (PMID: 19409525). Three alternate residues at position Arg39 (R39) have been previously reported as likely pathogenic/pathogenic suggesting the residue is critical to protein function (ClinVar ID = 199665;1066384; 65449). There is a small physicochemical difference between arginine and histidine. ACTA2, in which the variant was identified, is a gene with a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in at least four unrelated individuals with thoracic aortic aneurysm with dissection (TAAD) with/without a history of stroke (PMID:19409525, 27611364, 29907982). The variant has been reported to segregate with TAAD in affected family members from two unrelated families (PMID: 19409525). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.867). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM1, PM2_Supporting, PP1_Strong, PP2, PP3, PS4_Supporting
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000533011	SCV005417725	pathogenic	Aortic aneurysm, familial thoracic 6		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Moderate+PP2+PS4+PM5_Strong+PP4