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NM_015178.3(RHOBTB2):c.1453C>T (p.Arg485Cys) AND Developmental and epileptic encephalopathy, 64

Germline classification:
Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:
Feb 10, 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:
RCV000755717.12

Allele description [Variation Report for NM_015178.3(RHOBTB2):c.1453C>T (p.Arg485Cys)]

NM_015178.3(RHOBTB2):c.1453C>T (p.Arg485Cys)

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.1453C>T (p.Arg485Cys)
HGVS:
  • NC_000008.11:g.23007698C>T
  • NG_047133.1:g.25441C>T
  • NM_001160036.2:c.1519C>T
  • NM_001160037.2:c.1474C>T
  • NM_001374791.1:c.1453C>T
  • NM_015178.3:c.1453C>TMANE SELECT
  • NP_001153508.1:p.Arg507Cys
  • NP_001153509.1:p.Arg492Cys
  • NP_001361720.1:p.Arg485Cys
  • NP_055993.2:p.Arg485Cys
  • NC_000008.10:g.22865211C>T
  • NM_001160036.1:c.1519C>T
Protein change:
R485C
Links:
dbSNP: rs1563292586
NCBI 1000 Genomes Browser:
rs1563292586
Molecular consequence:
  • NM_001160036.2:c.1519C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001160037.2:c.1474C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374791.1:c.1453C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015178.3:c.1453C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Developmental and epileptic encephalopathy, 64
Synonyms:
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 64
Identifiers:
MONDO: MONDO:0033373; MedGen: C4693899; OMIM: 618004

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000883194SIB Swiss Institute of Bioinformatics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Oct 15, 2018)
unknowncuration

PubMed (2)
[See all records that cite these PMIDs]

SCV001150238Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
criteria provided, single submitter

(Classification criteria August 2017)
Pathogenic
(Aug 7, 2019)
de novoclinical testing

Citation Link,

SCV002549849Institute of Human Genetics, University of Leipzig Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jul 4, 2022)
de novoclinical testing

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

SCV004014710Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)
Pathogenic
(Feb 10, 2023)
unknownclinical testing

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

Citation Link,

SCV004803178Institute of Human Genetics, Heidelberg University
no assertion criteria provided
Likely pathogenic
(May 15, 2020)
de novoclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyes1not providednot provided1not providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing, curation

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

RHOBTB2 Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood.

Zagaglia S, Steel D, Krithika S, Hernandez-Hernandez L, Custodio HM, Gorman KM, Vezyroglou A, Møller RS, King MD, Hammer TB, Spaull R, Fazeli W, Bartolomaeus T, Doummar D, Keren B, Mignot C, Bednarek N, Cross JH, Mallick AA, Sanchis-Juan A, Basu A, Raymond FL, et al.

Neurology. 2021 Mar 16;96(11):e1539-e1550. doi: 10.1212/WNL.0000000000011543. Epub 2021 Jan 27.

PubMed [citation]
PMID:
33504645
PMCID:
PMC8032376
See all PubMed Citations (5)

Details of each submission

From SIB Swiss Institute of Bioinformatics, SCV000883194.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

This variant is interpreted as Likely Pathogenic, for Epileptic encephalopathy, early infantile, 64, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS2 => De novo (paternity and maternity confirmed) (https://www.ncbi.nlm.nih.gov/pubmed/29768694).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001150238.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyes1bloodnot provided1not providednot providednot provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002549849.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2, PS4_MOD, PM1, PM2_SUP, PP3

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services, Illumina, SCV004014710.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

The RHOBTB2 c.1519C>T (p.Arg507Cys) missense variant results in the substitution of arginine at amino acid position 507 with cysteine. This variant has been reported in a heterozygous state in a total of three individuals with developmental and epileptic encephalopathy, including two individuals in whom the variant was found in a de novo state and one individual in whom the inhertiance of the variant was unknown (PMID: 29768694; PMID: 33619735; PMID: 33504645). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Transient expression in Neuro2a cells demonstrated that the p.Arg507Cys variant was significantly more abundant than wild-type and escaped protesomal degradation. Co-expression of CUL3 with RHOBTB2 resulted in a decrease in levels of wild-type RHOBTB2 but not that of the variant protein suggesting that the variant affects degradation by the CUL3 ubiquitin ligase complex (PMID: 29768694). The Arg507 residue is located at the C-terminal end of the first BTB domain with several clinically significant missense variants reported in the vicinity (PMID: 29276004). Based on the available evidence, the c.1519C>T (p.Arg507Cys) variant is classified as pathogenic for developmental and epileptic encephalopathy.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Institute of Human Genetics, Heidelberg University, SCV004803178.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024