ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 196 of the ACTB protein (p.Arg196His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Baraitser-Winter syndrome (PMID: 22366783). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29599). 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 ACTB protein function with a negative predictive value of 80%. This variant disrupts the p.Arg196 amino acid residue in ACTB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22366783, 23756437, 25052316). 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.

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 27868373, 22366783, 27625340, 25052316, 27096712, 10928857, 32234145)

Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novoo in similarly affected indivisual (PMID: 26583190, 2236678, PS2, PS4).The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg196Cys) has been reported as pathogenic/likely pathogenic with strong evidence (PMID:26583190, 22366783, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.817, 3Cnet: 0.884, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

The c.587G>A (p.R196H) alteration is located in exon 4 (coding exon 3) of the ACTB gene. This alteration results from a G to A substitution at nucleotide position 587, causing the arginine (R) at amino acid position 196 to be replaced by a histidine (H)._x000D_ _x000D_ for ACTB-related Baraitser-Winter syndrome; however, its clinical significance for ACTB-related pleiotropic malformation syndrome is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in multiple individuals diagnosed with Baraister-Winter syndrome and has been determined to be the result of a de novo mutation in three individuals diagnosed with Baraitser-Winter syndrome (Rivière, 2012; Cianci, 2017). Another alteration at the same codon, c.586C>T (p.R196C), has been reported in a cohort of individuals with clinical features consistent with Baraister-Winter syndrome (Rivière, 2012). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.