ClinVar Genomic variation as it relates to human health

The p.R258C pathogenic mutation (also known as c.772C>T), located in coding exon 6 of the ACTA2 gene, results from a C to T substitution at nucleotide position 772. The arginine at codon 258 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was found to segregate with disease in two unrelated families with familial thoracic aortic aneurysms and dissections (TAAD) and premature ischemic strokes (Guo DC et al. Am J Hum Genet. 2009;84(5):617-27). This variant was also reported as de novo in one family with TAAD (Guo et al 2009). In addition, this variant very likely resulted from a de novo event in one family tested in our laboratory. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Reported in association with premature stroke, PDA and TAAD in multiple unrelated probands and families (PMID: 25644172, 19409525, 25759435); Published functional studies demonstrate a damaging effect as this variant disrupts actin dynamics and leads to contractile dysfunction (PMID: 26153420, 28652363); 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: 17994018, 33513575, 26934405, 27879251, 28652363, 30341550, 30300893, 28848449, 25759435, 36053285, 34498425, 35567597, 37587538, 32814715, 33990081, 34546411, 34600884, 30880160, 36194209, 32464348, 32997990, 33776470, 34062765, 25644172, 26153420, PetrovI2022[Article], 19409525)

The c.772C>T (p.Arg258Cys) variant of the ACTA2 gene replaces arginine with cysteine at codon 258. This sequence change has been reported in multiple individuals with thoracic aortic aneurysms and dissections (PMID 19409525, 25644172, 28652363, 33513575, 37042257, 36053285). This variant shows segregation within family members with incomplete penetrance (17994018). A confirmed de novo occurrence of this variant has been reported (PMID: 19409525). Experimental analysis of this variant in patient-specific smooth muscle cells demonstrated a detrimental impact on protein stability and contractile function (PMID 26153420). A detrimental impact on cytoskeletal functions using patient-specific fibroblasts has also been reported (PMID 28652363). Computational evidence suggests this variant is detrimental to ACTA2 protein function (REVEL score 0.932). The frequency of this variant in the general population database (gnomAD) is rare (0. 0.003%). Another variant disrupting the same amino acid has been interpreted as pathogenic (ClinVar ID: 18277). Clinvar contains an entry for this variant (Variation ID: 18278). Based on the available evidence, the c.772C>T (p.Arg258Cys) variant of the ACTA2 gene is classified as pathogenic.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the ACTA2 protein (p.Arg258Cys). This variant is present in population databases (rs121434528, gnomAD 0.007%). This missense change has been observed in individual(s) with nonsyndromic heritable thoracic aortic disorder and thoracic aortic aneurysms and patent ductus arteriosus (PMID: 17994018, 19409525, 25644172). 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: 18278). 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%. Experimental studies have shown that this missense change affects ACTA2 function (PMID: 26153420). For these reasons, this variant has been classified as Pathogenic.

This sequence change in ACTA2 is predicted to replace arginine with cysteine at codon 258, p.(Arg258Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the SM alpha-actin SD4 domain (PMID: 19409525). There is a large physicochemical difference between arginine and cysteine. ACTA2, in which the variant was identified, is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1). This variant is present in a single individual from the European (non-Finnish) population in the population database gnomAD v2.1 (1/68,040 alleles), which is consistent with ACTA2-related disease. This variant has been reported in multiple probands with thoracic aortic aneurysm and aortic dissection (TAAD) with/without premature stroke, and segregates with disease in multiple families (PMID: 19409525, 25644172, 25759435, 37042257). The variant has also been identified as a de novo occurrence with confirmed parental relationships in one family with cerebral arteriopathy and mild TAAD and as a de novo occurrence with unconfirmed parental relationships in one individual with TAAD (PMID: 19409525, 33513575). This variant alters protein function in a dominant negative manner in both in vitro functional assays and patient fibroblasts (PMID: 26153420, 28652363). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.932). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4_Moderate, PS2_Moderate/PM6, PP1_Moderate, PP3_Moderate, PS3_Supporting, PM2_Supporting, PP2, PP4.

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) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygote). (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) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in at least 10 unrelated individuals with thoracic aortic disorders and has been classified as pathogenic (ClinVar, PMID:33513575, PMID:19409525, PMID:25644172, PMID:36053285). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign