Submissions for variant NM_015178.3(RHOBTB2):c.1382G>A (p.Arg461His)

dbSNP: rs1554504663

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000656372	SCV000883204	pathogenic	Developmental and epileptic encephalopathy, 64	2018-10-15	criteria provided, single submitter	curation	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. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29276004). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29276004) (https://www.ncbi.nlm.nih.gov/pubmed/29768694). PS2 => De novo (paternity and maternity confirmed) (https://www.ncbi.nlm.nih.gov/pubmed/29276004) (https://www.ncbi.nlm.nih.gov/pubmed/29768694).
Undiagnosed Diseases Network, NIH	RCV000656372	SCV000926982	likely pathogenic	Developmental and epileptic encephalopathy, 64	2018-12-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000656372	SCV001150237	pathogenic	Developmental and epileptic encephalopathy, 64	2019-10-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001265836	SCV001444008	likely pathogenic	Inborn genetic diseases	2018-01-04	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268457	SCV001447407	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001268457	SCV001823890	pathogenic	not provided	2023-05-16	criteria provided, single submitter	clinical testing	Not observed 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: 28856709, 33098801, 33619735, 32653842, 29276004, 29768694, 32337345, 35872528, 35586607, 35231114, 34356170, 31957018)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001268457	SCV002238192	pathogenic	not provided	2023-06-05	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with RHOBTB2-related conditions (PMID: 28856709, 29276004). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 545417). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RHOBTB2 protein function. Experimental studies have shown that this missense change affects RHOBTB2 function (PMID: 29276004). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 483 of the RHOBTB2 protein (p.Arg483His).
MGZ Medical Genetics Center	RCV000656372	SCV002579472	likely pathogenic	Developmental and epileptic encephalopathy, 64	2021-08-18	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000656372	SCV002768034	pathogenic	Developmental and epileptic encephalopathy, 64	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 64 (MIM#618004). (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 histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER) in the first BTB domain (PMID: 29276004). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent pathogenic variant (often referred to as p.(Arg483His) in an alternative transcript) that has previously been identified in multiple de novo individuals with developmental and epileptic encephalopathy 64 (MIM#618004) (ClinVar, DECIPHER, PMID: 29276004). (SP) 1102 - Strong phenotype match for this individual. (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
Neuberg Centre For Genomic Medicine, NCGM	RCV000656372	SCV005042968	pathogenic	Developmental and epileptic encephalopathy, 64		criteria provided, single submitter	clinical testing	The missense c.1382G>Ap.Arg461His variant in RHOBTB2 gene has been reported previously in heterozygous state in individuals affected with Developmental and Epileptic Encephalopathy Straub J et al., 2018. Experimental studies have shown that this missense change affects RHOBTB2 function Straub J et al., 2018. This variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. The amino acid Arg at position 461 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg461His in RHOBTB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000656372	SCV005397875	pathogenic	Developmental and epileptic encephalopathy, 64	2022-11-23	criteria provided, single submitter	clinical testing
OMIM	RCV000656372	SCV000778373	pathogenic	Developmental and epileptic encephalopathy, 64	2020-11-17	no assertion criteria provided	literature only