ClinVar Miner

Submissions for variant NM_001613.4(ACTA2):c.116G>A (p.Arg39His) (rs794728021)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181015 SCV000233289 likely pathogenic not provided 2018-04-10 criteria provided, single submitter clinical testing The R39H variant in the ACTA2 gene has been reported in multiple individuals in two unrelated families with a history of TAAD, premature CAD, and early onset stroke (<20 years) (Guo et al., 2009) and in a patient with post-partum aortic dissection (Regalado et al., 2014). This variant has also been reported in a cohort of patients with Marfan syndrome or aortopathy (Yang et al., 2016); however, specific clinical and segregation information was not provided. The R39H variant is not observed in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A missense variant in the same residue (R39C) has been reported in the Human Gene Mutation Database in association with TAAD (Stenson et al., 2014), supporting the functional importance of this residue of the protein. Nonetheless, the R39H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Invitae RCV000533011 SCV000646311 pathogenic Aortic aneurysm, familial thoracic 6 2017-07-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 39 of the ACTA2 protein (p.Arg39His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with aortic dissections in two families (PMID: 19409525). In addition, this variant has been found in unrelated individuals with aortic dissections (PMID: 27611364, Invitae). ClinVar contains an entry for this variant (Variation ID: 199666). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). A different missense substitution at this codon (p.Arg39Cys) has been determined to be pathogenic (PMID:  21248741, 21733706, 21937134, 24243736, 25644172, 25759435). This suggests that the arginine residue is critical for ACTA2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000621097 SCV000738463 likely pathogenic Cardiovascular phenotype 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

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