NM_015178.3(RHOBTB2):c.1382G>A (p.Arg461His) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jun 5, 2023
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:: RCV001268457.7

Allele description [Variation Report for NM_015178.3(RHOBTB2):c.1382G>A (p.Arg461His)]

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

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.1382G>A (p.Arg461His)

HGVS:

NC_000008.11:g.23007627G>A
NG_047133.1:g.25370G>A
NM_001160036.2:c.1448G>A
NM_001160037.2:c.1403G>A
NM_001374791.1:c.1382G>A
NM_015178.3:c.1382G>AMANE SELECT
NP_001153508.1:p.Arg483His
NP_001153509.1:p.Arg468His
NP_001361720.1:p.Arg461His
NP_055993.2:p.Arg461His
NC_000008.10:g.22865140G>A
NC_000008.10:g.22865140G>A
NM_001160036.1:c.1448G>A
NM_015178.2:c.1382G>A

Protein change:

R461H; ARG483HIS

Links:

OMIM: 607352.0001; dbSNP: rs1554504663

NCBI 1000 Genomes Browser:

rs1554504663

Molecular consequence:

NM_001160036.2:c.1448G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160037.2:c.1403G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374791.1:c.1382G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_015178.3:c.1382G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001447407	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001823890	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 16, 2023)	germline	clinical testing	Citation Link,
SCV002238192	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 5, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28856709, 29276004, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001447407

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 23, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001823890

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 16, 2023)

germline

clinical testing

Citation Link,

SCV002238192

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 5, 2023)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy.

Yoo Y, Jung J, Lee YN, Lee Y, Cho H, Na E, Hong J, Kim E, Lee JS, Lee JS, Hong C, Park SY, Wie J, Miller K, Shur N, Clow C, Ebel RS, DeBrosse SD, Henderson LB, Willaert R, Castaldi C, Tikhonova I, et al.

Ann Neurol. 2017 Sep;82(3):466-478. doi: 10.1002/ana.25032.

PubMed [citation]

PMID:: 28856709

See all PubMed Citations (4)

Details of each submission

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447407.1

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

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

From GeneDx, SCV001823890.2

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

Description

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)

#	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, SCV002238192.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RHOBTB2 function (PMID: 29276004). 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. ClinVar contains an entry for this variant (Variation ID: 545417). 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. 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).

#	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: May 12, 2024

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