dbSNP rs1554504684: RHOBTB2:p.Arg489Gln (chr8-23007711-G-A) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 8.15

Variant links:

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]

RHOBTB2 links:

ENSG00000245025 (HGNC:58239):

ENSG00000245025 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 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].

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 rank	MANE	Protein	UniProt
RHOBTB2	NM_015178.3 link	c.1466G>A	p.Arg489Gln	missense_variant	Exon 5 of 10	ENST00000251822.7	NP_055993.2	Q9BYZ6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOBTB2	ENST00000251822.7 link	c.1466G>A	p.Arg489Gln	missense_variant	Exon 5 of 10	1	NM_015178.3	ENSP00000251822.7		Q9BYZ6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 64

Pathogenic:6

Nov 17, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 17, 2023

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2021

Pediatrics, MediClubGeorgia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 19, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. 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). -

Nov 09, 2022

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg511Gln variant in the RHOBTB2 gene was identified de novo in this individual and has previously been identified de novo in at least 4 additional unrelated individuals with RHOBTB2-related developmental and epileptic encephalopathy (Belal 2018, Straub 2018, Spagnoli 2020). The p.Arg511Gln variant has been submitted to ClinVar (Variation ID: 545418, ncbi.nlm.nih.gov/clinvar/). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Well-established functional studies of this variant suggest a deleterious effect to the protein that is sufficient to be disease-causing (Belal 2018). Additionally, a different amino acid changes at this residue (p.Arg511Trp) has been previously reported de novo in two unrelated individuals with RHOBTB2-related developmental and epileptic encephalopathy (Straub 2018). Using ACMG guidelines, this variant was classified as pathogenic for autosomal dominant RHOBTB2-related developmental and epileptic encephalopathy (ACMG evidence codes used: PS2_very strong, PS3, PM5, PM2_supporting). -

not provided

Pathogenic:3

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 545418). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RHOBTB2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RHOBTB2 function (PMID: 29768694). 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. For these reasons, this variant has been classified as Pathogenic. -

Aug 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RHOBTB2: PS2:Very Strong, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -

Chorea;C0013421:Dystonic disorder

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Inborn genetic diseases

Pathogenic:1

Sep 09, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

.;.;T

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Uncertain

0.13

MutationAssessor

Uncertain

2.8

.;.;M

PrimateAI

Pathogenic

0.81

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over