ClinVar Genomic variation as it relates to human health

Identified in individuals with aortic aneurysms and multisystemic smooth muscle dysfunction syndrome referred for genetic testing at GeneDx in the published literature (PMID: 27481187, 23613326, 27567161, 27244053); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30300893, 27567161, 25759435, 27244053, 29300374, 24621862, 29875232, 33199432, 33342581, 34193752, 36909460, 35878552, 37886459, 27481187, 23613326)

Variant summary: ACTA2 c.535C>T (p.Arg179Cys) results in a non-conservative amino acid change in the encoded protein sequence indicated to be located near a key protein-protein interaction site (Moreno_2016). Five of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be functionally asssessed. The variant was absent in 121348 control chromosomes (ExAC). Multiple publications have cited the variant in affected individuals presenting with a multisystemic smooth muscle dysfunction syndrome (MSMDS) and aortic event. Multiple studies indicate the variant was a de novo occurrence (Meuwissen_2012 and Moreno_2016). In addition, other variants affecting the same codon, Arg179His and Arg179Lys, have been reported in affected individuals indicating a potential mutational hot spot. One clinical diagnostic laboratory has submitted a clinical-significance assessments of "likely pathogenic" for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Arg179Cys variant has been previously reported as de novo in patients with multisystemic smooth muscle dysfunction syndrome (MSMDS) disorder (PMID: 23613326, 27567161, 27244053, 27481187, 29875232). Multiple missense alterations at the same amino acid residue, including the recurrent p.Arg179His substitution, have been reported in association with MSMDS (PMID: 22831780, 24621862, 20734336, 26034244, 22752479, 24998021, 22946110, 24293535). Functional in-vitro studies variant using a baculovirus/insect cell system showed the p.Arg179Cys variant severely affects smooth muscle alpha-actin functions (PMID: 26153420). The p.Arg179Cys variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. In silico analyses support a deleterious effect of the p.Arg179Cys variant on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.535C>T (p.Arg179Cys) variant is classified as Pathogenic.

This variant disrupts the p.Arg179 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20734336, 22752479, 22946110, 24293535, 24621862, 24998021, 26034244). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt ACTA2 protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 265026). This missense change has been observed in individual(s) with multisystemic smooth muscle dysfunction syndrome and childhood cardiovascular, autonomic and brain anomalies and aortic dissection or aneurysm (PMID: 23613326, 25759435, 27481187, 27567161). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 179 of the ACTA2 protein (p.Arg179Cys).

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with familial thoracic aortic aneurysm 6 (MIM#611788), Moyamoya disease 5 (MIM#614042) and multisystemic smooth muscle dysfunction syndrome (MIM#613834) (PMID: 27551047, 28652363). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Actin domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Alternative changes to leucine, histidine and serine have been reported in individuals with smooth muscle dysfunction syndrome (ClinVar, PMID: 29300374). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent pathogenic variant in individuals with multisystemic smooth muscle dysfunction syndrome (ClinVar, PMID: 23613326, PMID: 29300374). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign