NM_015178.3(RHOBTB2):c.1466G>A (p.Arg489Gln) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 22, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001311325.27

Allele description

NM_015178.3(RHOBTB2):c.1466G>A (p.Arg489Gln)

Gene:

RHOBTB2:Rho related BTB domain containing 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8p21.3

Genomic location:

Preferred name:

NM_015178.3(RHOBTB2):c.1466G>A (p.Arg489Gln)

HGVS:

NC_000008.11:g.23007711G>A
NG_047133.1:g.25454G>A
NM_001160036.2:c.1532G>A
NM_001160037.2:c.1487G>A
NM_001374791.1:c.1466G>A
NM_015178.3:c.1466G>AMANE SELECT
NP_001153508.1:p.Arg511Gln
NP_001153509.1:p.Arg496Gln
NP_001361720.1:p.Arg489Gln
NP_055993.2:p.Arg489Gln
NC_000008.10:g.22865224G>A
NC_000008.10:g.22865224G>A
NM_001160036.1:c.1532G>A
p.(Arg511Gln)

Protein change:

R489Q; ARG511GLN

Links:

OMIM: 607352.0002; dbSNP: rs1554504684

NCBI 1000 Genomes Browser:

rs1554504684

Molecular consequence:

NM_001160036.2:c.1532G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160037.2:c.1487G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374791.1:c.1466G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_015178.3:c.1466G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001501452	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Aug 1, 2020)	germline	clinical testing	Citation Link,
SCV001779817	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 31, 2022)	germline	clinical testing	Citation Link,
SCV002243949	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 22, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31780880, 29276004, 29768694, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001501452

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Aug 1, 2020)

germline

clinical testing

Citation Link,

SCV001779817

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 31, 2022)

germline

clinical testing

Citation Link,

SCV002243949

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 22, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients.

Fernández-Marmiesse A, Roca I, Díaz-Flores F, Cantarín V, Pérez-Poyato MS, Fontalba A, Laranjeira F, Quintans S, Moldovan O, Felgueroso B, Rodríguez-Pedreira M, Simón R, Camacho A, Quijada P, Ibanez-Mico S, Domingno MR, Benito C, Calvo R, Pérez-Cejas A, Carrasco ML, Ramos F, Couce ML, et al.

Front Neurosci. 2019;13:1135. doi: 10.3389/fnins.2019.01135.

PubMed [citation]

PMID:: 31780880
PMCID:: PMC6856296

Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila.

Straub J, Konrad EDH, Grüner J, Toutain A, Bok LA, Cho MT, Crawford HP, Dubbs H, Douglas G, Jobling R, Johnson D, Krock B, Mikati MA, Nesbitt A, Nicolai J, Phillips M, Poduri A, Ortiz-Gonzalez XR, Powis Z, Santani A, Smith L, Stegmann APA, et al.

Am J Hum Genet. 2018 Jan 4;102(1):44-57. doi: 10.1016/j.ajhg.2017.11.008. Epub 2017 Dec 21.

PubMed [citation]

PMID:: 29276004
PMCID:: PMC5777381

See all PubMed Citations (4)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001501452.20

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From GeneDx, SCV001779817.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002243949.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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