rs1554504684

Positions:

• chr8-23007711-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_015178.3(RHOBTB2):​c.1466G>A​(p.Arg489Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R489G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHOBTB2 NM_015178.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.15

Genes affected

RHOBTB2 (HGNC:18756): (Rho related BTB domain containing 2) The protein encoded by this gene is a small Rho GTPase and a candidate tumor suppressor. The encoded protein interacts with the cullin-3 protein, a ubiquitin E3 ligase necessary for mitotic cell division. This protein inhibits the growth and spread of some types of breast cancer. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

ENSG00000245025 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-23007710-C-G is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RHOBTB2. . Gene score misZ 2.6599 (greater than the threshold 3.09). Trascript score misZ 3.127 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 64.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784
• PP5: Variant 8-23007711-G-A is Pathogenic according to our data. Variant chr8-23007711-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 545418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-23007711-G-A is described in Lovd as [Pathogenic]. Variant chr8-23007711-G-A is described in Lovd as [Likely_pathogenic]. Variant chr8-23007711-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHOBTB2	NM_015178.3	c.1466G>A	p.Arg489Gln	missense_variant	5/10	ENST00000251822.7	NP_055993.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHOBTB2	ENST00000251822.7	c.1466G>A	p.Arg489Gln	missense_variant	5/10	1	NM_015178.3	ENSP00000251822.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 64 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 19, 2021	This variant was identified as de novo (maternity and paternity confirmed). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 17, 2023	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Pediatrics, MediClubGeorgia	Jan 01, 2021	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 17, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 22, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	RHOBTB2: PS2:Very Strong, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -

Chorea;C0013421:Dystonic disorder Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	.;.;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.8	.;.;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.094	T;T;T
Sift4G	Benign	0.061	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.68
MutPred		0.47		.;.;Loss of MoRF binding (P = 0.0132);
MVP		0.73
MPC		1.4
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.30
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554504684; hg19: chr8-22865224; COSMIC: COSV52572914; COSMIC: COSV52572914;