ClinVar Genomic variation as it relates to human health

This variant is interpreted as Pathogenic, for Epileptic encephalopathy, early infantile, 64, autosomal dominant. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Supporting => PS4 downgraded in strength to Supporting (https://www.ncbi.nlm.nih.gov/pubmed/29768694) (https://www.ncbi.nlm.nih.gov/pubmed/29276004). PS2 => De novo (paternity and maternity confirmed) (https://www.ncbi.nlm.nih.gov/pubmed/29276004) (https://www.ncbi.nlm.nih.gov/pubmed/29768694). PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29276004).

The RHOBTB2 variant c.1532G>A p.(Arg511Gln) causes an amino acid change from Arg to Gln at position 511. This variant has been previously reported as disease-causing for Rett-like syndrome, this variant de novo in different patients. The variant is absent in population databases. SIFT - deleterious, PolyPhen - Probably Damaging, FATHMM pred - Tolerated, MutationAssessor - Medium, MutationTaster - diseases causing, Provean - Neutral. On Clinvar this variant is submitted by 4 submitter: as 3 Pathogenic, 1 Likely Pathogenic.

This variant was identified as de novo (maternity and paternity confirmed).

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29768694, 29276004, 32337345, 32810689, 32581362)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 511 of the RHOBTB2 protein (p.Arg511Gln). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg511 amino acid residue in RHOBTB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29276004, 31780880). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RHOBTB2 function (PMID: 29768694). 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 RHOBTB2 protein function. ClinVar contains an entry for this variant (Variation ID: 545418). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 29276004, 29768694). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).

The c.1532G>A (p.R511Q) alteration is located in exon 7 (coding exon 5) of the RHOBTB2 gene. This alteration results from a G to A substitution at nucleotide position 1532, causing the arginine (R) at amino acid position 511 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation or germline mosaicism in multiple individuals with RHOBTB2-related developmental and epileptic encephalopathy (Straub, 2017; Belal, 2018; Fernández-Marmiesse, 2019; Zagaglia, 2021; Knijnenburg, 2020). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.