VCV000545417.20 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(12)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 545417 Accession: VCV000545417.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p21.3 8: 23007627 (GRCh38) [ NCBI UCSC ] 8: 22865140 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 12, 2018	Nov 17, 2024	Jun 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_015178.3:c.1382G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055993.2:p.Arg461His	missense
NM_001160036.2:c.1448G>A	NP_001153508.1:p.Arg483His	missense
NM_001160037.2:c.1403G>A	NP_001153509.1:p.Arg468His	missense
NM_001374791.1:c.1382G>A	NP_001361720.1:p.Arg461His	missense
NM_015178.2:c.1382G>A
NC_000008.11:g.23007627G>A
NC_000008.10:g.22865140G>A
NG_047133.1:g.25370G>A

... more HGVS ... less HGVS

Protein change

R483H, R461H, R468H

Other names

Canonical SPDI

NC_000008.11:23007626:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 607352.0001 dbSNP: rs1554504663 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RHOBTB2		-	-	GRCh38 GRCh37	673	760

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Developmental and epileptic encephalopathy, 64	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Nov 23, 2022	RCV000656372.16
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Jan 4, 2018	RCV001265836.2
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 5, 2023	RCV001268457.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 15, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Developmental and epileptic encephalopathy, 64 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000883204.1 First in ClinVar: Jun 12, 2018 Last updated: Jun 12, 2018	Publications: PubMed (2) PubMed: 29276004‚ 29768694 Comment: 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 … (more) 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. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29276004). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29276004) (https://www.ncbi.nlm.nih.gov/pubmed/29768694). PS2 => De novo (paternity and maternity confirmed) (https://www.ncbi.nlm.nih.gov/pubmed/29276004) (https://www.ncbi.nlm.nih.gov/pubmed/29768694). (less)
Likely pathogenic (Dec 03, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 64 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Accession: SCV000926982.1 First in ClinVar: Jul 21, 2019 Last updated: Jul 21, 2019	Number of individuals with the variant: 1 Clinical Features: Seizures (present) , Nevus flammeus (present) , Global developmental delay (present) , Gastroesophageal reflux (present) , Dystonia (present) , Constipation (present) , Central hypotonia (present) … (more) Seizures (present) , Nevus flammeus (present) , Global developmental delay (present) , Gastroesophageal reflux (present) , Dystonia (present) , Constipation (present) , Central hypotonia (present) , Cafe-au-lait spot (present) , Abnormality of movement (present) , 2-3 toe syndactyly (present) (less) Age: 0-9 years Sex: male Ethnicity/Population group: White Tissue: blood Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC Date variant was reported to submitter: 2018-07-31 Testing laboratory interpretation: Likely pathogenic
Pathogenic (Oct 18, 2019)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Developmental and epileptic encephalopathy, 64 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001150237.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Sex: female Tissue: blood
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447407.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Anemia (present) , Epileptic encephalopathy (present) , Seizure (present) , Global developmental delay (present) Sex: male
Likely pathogenic (Aug 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 64 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579472.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS2, PS4_MOD, PM2_SUP	Number of individuals with the variant: 1 Sex: male
Pathogenic (May 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 64 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768034.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 29276004 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 64 (MIM#618004). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER) in the first BTB domain (PMID: 29276004). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent pathogenic variant (often referred to as p.(Arg483His) in an alternative transcript) that has previously been identified in multiple de novo individuals with developmental and epileptic encephalopathy 64 (MIM#618004) (ClinVar, DECIPHER, PMID: 29276004). (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Likely pathogenic (Jan 04, 2018)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV001444008.2 First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023	Publications: PubMed (2) PubMed: 29276004‚ 18298893 Number of individuals with the variant: 1 Clinical Features: Telecanthus (present) , Long philtrum (present) , Constipation (present) , Ptosis (present) , Seizures (present) , Muscle weakness (present) , Malar flattening (present) , Epicanthus … (more) Telecanthus (present) , Long philtrum (present) , Constipation (present) , Ptosis (present) , Seizures (present) , Muscle weakness (present) , Malar flattening (present) , Epicanthus (present) , Muscular hypotonia (present) , Wide nasal bridge (present) , Downslanted palpebral fissures (present) , Global developmental delay (present) , Gastroesophageal reflux (present) , Feeding difficulties (present) , Deeply set eye (present) , Almond-shaped palpebral fissure (present) , Prominent nasal tip (present) , Prominent metopic ridge (present) , Hyperpigmented/hypopigmented macules (present) , Hyporeflexia (present) (less) Sex: male Ethnicity/Population group: Caucasian/Irish/English/Italian
Pathogenic (May 16, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001823890.2 First in ClinVar: Sep 08, 2021 Last updated: May 27, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Jun 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002238192.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 29276004‚ 28856709 Comment: 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 … (more) 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). (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 64 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005042968.1 First in ClinVar: May 12, 2024 Last updated: May 12, 2024	Comment: The missense c.1382G>Ap.Arg461His variant in RHOBTB2 gene has been reported previously in heterozygous state in individuals affected with Developmental and Epileptic Encephalopathy Straub J et … (more) The missense c.1382G>Ap.Arg461His variant in RHOBTB2 gene has been reported previously in heterozygous state in individuals affected with Developmental and Epileptic Encephalopathy Straub J et al., 2018. Experimental studies have shown that this missense change affects RHOBTB2 function Straub J et al., 2018. This variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. The amino acid Arg at position 461 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg461His in RHOBTB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of the nervous system (present)
Pathogenic (Nov 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 64 Affected status: yes Allele origin: de novo	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV005397875.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024
Pathogenic (Nov 17, 2020)	no assertion criteria provided Method: literature only	DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 64 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000778373.2 First in ClinVar: Jun 12, 2018 Last updated: Nov 21, 2020	Publications: PubMed (1) PubMed: 29276004 Comment on evidence: In 4 unrelated children (individuals 1-4) with developmental and epileptic encephalopathy-64 (DEE64; 618004), Straub et al. (2018) identified a de novo heterozygous c.1448G-A transition (c.1448G-A, … (more) In 4 unrelated children (individuals 1-4) with developmental and epileptic encephalopathy-64 (DEE64; 618004), Straub et al. (2018) identified a de novo heterozygous c.1448G-A transition (c.1448G-A, NM_001160036.1) in exon 7 of the RHOBTB2 gene, resulting in an arg483-to-his (R483H) substitution at a highly conserved residue in the first BTB domain. Molecular modeling suggested that the R483H mutation caused destabilization of the first BTB domain. The mutation, which was found by trio-based exome sequencing, was not found in the ExAC or gnomAD databases. The patients had onset of seizures between 2 and 6 months of age. (less)
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Comment:

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. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29276004). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29276004) (https://www.ncbi.nlm.nih.gov/pubmed/29768694). PS2 => De novo (paternity and maternity confirmed) (https://www.ncbi.nlm.nih.gov/pubmed/29276004) (https://www.ncbi.nlm.nih.gov/pubmed/29768694).

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 64 (MIM#618004). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER) in the first BTB domain (PMID: 29276004). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent pathogenic variant (often referred to as p.(Arg483His) in an alternative transcript) that has previously been identified in multiple de novo individuals with developmental and epileptic encephalopathy 64 (MIM#618004) (ClinVar, DECIPHER, PMID: 29276004). (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

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)

Comment:

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).

Comment:

The missense c.1382G>Ap.Arg461His variant in RHOBTB2 gene has been reported previously in heterozygous state in individuals affected with Developmental and Epileptic Encephalopathy Straub J et al., 2018. Experimental studies have shown that this missense change affects RHOBTB2 function Straub J et al., 2018. This variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. The amino acid Arg at position 461 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg461His in RHOBTB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
De novo variants in RHOBTB2, an atypical Rho GTPase gene, cause epileptic encephalopathy.	Belal H	Human mutation	2018	PMID: 29768694
Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila.	Straub J	American journal of human genetics	2018	PMID: 29276004
GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy.	Yoo Y	Annals of neurology	2017	PMID: 28856709
Rho GTPases of the RhoBTB subfamily and tumorigenesis.	Berthold J	Acta pharmacologica Sinica	2008	PMID: 18298893

Text-mined citations for rs1554504663 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554504663 ...