ClinVar Genomic variation as it relates to human health

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.87). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals, and observed in at least two similarly affected unrelated individuals (PMID: 24075189). Different missense changes at the same codon (p.Arg387Leu, p.Arg387Ser) have been reported to be associated with RARB-related disorder (ClinVar ID: VCV000088763 , VCV000430023 / PMID: 24075189). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Published functional studies demonstrate a gain-of-function effect on the resultant protein (Srour et al., 2013); 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: 24075189, 25457163, 27120018, 30790422, 30480585)

The c.1159C>T (p.R387C) alteration is located in exon 8 (coding exon 8) of the RARB gene. This alteration results from a C to T substitution at nucleotide position 1159, causing the arginine (R) at amino acid position 387 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The p.R387C alteration has been identified in three cases with features of anophthalmia/microphthalmia, severe developmental delay, progressive spasticity, Chiari I malformation, and feeding difficulties (Srour, 2013; Slavotinek, 2015). Srour et al. (2013) identified this de novo missense change in a fetus that was terminated because of a prenatal diagnosis of unilateral microphthalmia and left diaphragmatic hernia and also in a newborn who died within hours of birth with left diaphragmatic hernia, bilateral microphthalmia, and pulmonary hypoplasia. Slavotinek et al. (2015) reported a de novo p.R387C alteration in a patient with bilateral microphthalmia and unilateral coloboma, left diaphragmatic hernia, cleft palate, and a Chiari I malformation. Another variant at the same codon, p.R387S, has been identified in one individual with bilateral microphthalmia, corrected diaphragmatic hernia, intellectual disability, and spasticity (Chitayat, 2007; Srour, 2013). This amino acid position is highly conserved in available vertebrate species. The p.R387C amino acid is located in helix 11 of the C-terminal ligand-binding domain (Srour, 2013). When a ligand binds, the ligand-binding domain undergoes a conformational change in the receptor to induce a response, which serves as a molecular switch to activate transcriptional activity (Edwards, 2000). Functional analysis demonstrated that the p.R387C alteration induced a 2- to 3-fold increase in RARB transcriptional activity in response to retinoic acid ligands, suggestive of a gain-of-function mechanism (Srour, 2013). Functional analysis in transfected HEK293 cells demonstrated that the transcriptional response to retinoic acid was significantly increased, reaching a 28-fold induction for the p.R387C mutant compared to 9-fold for wildtype RARB (Srour, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

This variant disrupts the p.Arg387 amino acid residue in RARB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24075189). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects RARB function (PMID: 24075189). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 88762). This missense change has been observed in individual(s) with microphthalmia (PMID: 24075189, 27120018). 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 387 of the RARB protein (p.Arg387Cys).