Submissions for variant NM_015178.3(RHOBTB2):c.1453C>T (p.Arg485Cys)

dbSNP: rs1563292586

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000755717	SCV000883194	likely pathogenic	Developmental and epileptic encephalopathy, 64	2018-10-15	criteria provided, single submitter	curation	This variant is interpreted as Likely Pathogenic, for Epileptic encephalopathy, early infantile, 64, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS2 => De novo (paternity and maternity confirmed) (https://www.ncbi.nlm.nih.gov/pubmed/29768694).
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000755717	SCV001150238	pathogenic	Developmental and epileptic encephalopathy, 64	2019-08-07	criteria provided, single submitter	clinical testing
Invitae	RCV001052516	SCV001216728	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 507 of the RHOBTB2 protein (p.Arg507Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RHOBTB2-related conditions (PMID: 33504645, 33619735; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 617912). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001052516	SCV001501451	likely pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	RHOBTB2: PS2, PM2, PS4:Moderate
Institute of Human Genetics, University of Leipzig Medical Center	RCV000755717	SCV002549849	likely pathogenic	Developmental and epileptic encephalopathy, 64	2022-07-04	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2, PS4_MOD, PM1, PM2_SUP, PP3
Illumina Laboratory Services, Illumina	RCV000755717	SCV004014710	pathogenic	Developmental and epileptic encephalopathy, 64	2023-02-10	criteria provided, single submitter	clinical testing	The RHOBTB2 c.1519C>T (p.Arg507Cys) missense variant results in the substitution of arginine at amino acid position 507 with cysteine. This variant has been reported in a heterozygous state in a total of three individuals with developmental and epileptic encephalopathy, including two individuals in whom the variant was found in a de novo state and one individual in whom the inhertiance of the variant was unknown (PMID: 29768694; PMID: 33619735; PMID: 33504645). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Transient expression in Neuro2a cells demonstrated that the p.Arg507Cys variant was significantly more abundant than wild-type and escaped protesomal degradation. Co-expression of CUL3 with RHOBTB2 resulted in a decrease in levels of wild-type RHOBTB2 but not that of the variant protein suggesting that the variant affects degradation by the CUL3 ubiquitin ligase complex (PMID: 29768694). The Arg507 residue is located at the C-terminal end of the first BTB domain with several clinically significant missense variants reported in the vicinity (PMID: 29276004). Based on the available evidence, the c.1519C>T (p.Arg507Cys) variant is classified as pathogenic for developmental and epileptic encephalopathy.
GeneDx	RCV001052516	SCV004036902	pathogenic	not provided	2023-09-22	criteria provided, single submitter	clinical testing	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: 29768694, 37090824, 37165955, 33619735)
Institute of Human Genetics, Heidelberg University	RCV000755717	SCV004803178	likely pathogenic	Developmental and epileptic encephalopathy, 64	2020-05-15	no assertion criteria provided	clinical testing