NM_001353921.2(ARHGEF9):c.889C>T (p.Arg297Cys) AND Developmental and epileptic encephalopathy, 8

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 16, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001879754.3

Allele description [Variation Report for NM_001353921.2(ARHGEF9):c.889C>T (p.Arg297Cys)]

NM_001353921.2(ARHGEF9):c.889C>T (p.Arg297Cys)

Gene:

ARHGEF9:Cdc42 guanine nucleotide exchange factor 9 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq11.1

Genomic location:

Preferred name:

NM_001353921.2(ARHGEF9):c.889C>T (p.Arg297Cys)

HGVS:

NC_000023.11:g.63674094G>A
NG_016975.1:g.116453C>T
NM_001173479.2:c.709C>T
NM_001173480.2:c.562C>T
NM_001330495.2:c.805C>T
NM_001353921.2:c.889C>TMANE SELECT
NM_001353922.2:c.889C>T
NM_001353923.1:c.907C>T
NM_001353924.2:c.688C>T
NM_001353926.2:c.688C>T
NM_001353927.2:c.805C>T
NM_001353928.2:c.868C>T
NM_001369030.1:c.868C>T
NM_001369031.1:c.868C>T
NM_001369032.1:c.868C>T
NM_001369033.1:c.805C>T
NM_001369034.1:c.805C>T
NM_001369035.1:c.805C>T
NM_001369036.1:c.805C>T
NM_001369037.1:c.805C>T
NM_001369038.1:c.805C>T
NM_001369039.1:c.688C>T
NM_001369040.1:c.688C>T
NM_001369041.1:c.805C>T
NM_001369042.1:c.562C>T
NM_001369043.1:c.805C>T
NM_001369044.1:c.805C>T
NM_001369045.1:c.454C>T
NM_015185.3:c.868C>T
NP_001166950.1:p.Arg237Cys
NP_001166951.1:p.Arg188Cys
NP_001317424.1:p.Arg269Cys
NP_001340850.1:p.Arg297Cys
NP_001340851.1:p.Arg297Cys
NP_001340852.1:p.Arg303Cys
NP_001340853.1:p.Arg230Cys
NP_001340855.1:p.Arg230Cys
NP_001340856.1:p.Arg269Cys
NP_001340857.1:p.Arg290Cys
NP_001355959.1:p.Arg290Cys
NP_001355960.1:p.Arg290Cys
NP_001355961.1:p.Arg290Cys
NP_001355962.1:p.Arg269Cys
NP_001355963.1:p.Arg269Cys
NP_001355964.1:p.Arg269Cys
NP_001355965.1:p.Arg269Cys
NP_001355966.1:p.Arg269Cys
NP_001355967.1:p.Arg269Cys
NP_001355968.1:p.Arg230Cys
NP_001355969.1:p.Arg230Cys
NP_001355970.1:p.Arg269Cys
NP_001355971.1:p.Arg188Cys
NP_001355972.1:p.Arg269Cys
NP_001355973.1:p.Arg269Cys
NP_001355974.1:p.Arg152Cys
NP_056000.1:p.Arg290Cys
NC_000023.10:g.62893974G>A
NC_000023.10:g.62893974G>A
NM_015185.2:c.868C>T

Protein change:

R152C

Links:

dbSNP: rs2050115619

NCBI 1000 Genomes Browser:

rs2050115619

Molecular consequence:

NM_001173479.2:c.709C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173480.2:c.562C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330495.2:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353921.2:c.889C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353922.2:c.889C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353923.1:c.907C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353924.2:c.688C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353926.2:c.688C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353927.2:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353928.2:c.868C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369030.1:c.868C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369031.1:c.868C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369032.1:c.868C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369033.1:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369034.1:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369035.1:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369036.1:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369037.1:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369038.1:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369039.1:c.688C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369040.1:c.688C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369041.1:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369042.1:c.562C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369043.1:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369044.1:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369045.1:c.454C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_015185.3:c.868C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Developmental and epileptic encephalopathy, 8 (DEE8)
Synonyms:: HYPEREKPLEXIA AND EPILEPSY; Early infantile epileptic encephalopathy 8
Identifiers:: MONDO: MONDO:0010375; MedGen: C1845102; Orphanet: 163985; Orphanet: 2076; OMIM: 300607

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002138878	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 16, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25678704, 28589176, 29130122, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002138878

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 16, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Lipid binding defects and perturbed synaptogenic activity of a Collybistin R290H mutant that causes epilepsy and intellectual disability.

Papadopoulos T, Schemm R, Grubmüller H, Brose N.

J Biol Chem. 2015 Mar 27;290(13):8256-70. doi: 10.1074/jbc.M114.633024. Epub 2015 Feb 12.

PubMed [citation]

PMID:: 25678704
PMCID:: PMC4375481

ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation.

Alber M, Kalscheuer VM, Marco E, Sherr E, Lesca G, Till M, Gradek G, Wiesener A, Korenke C, Mercier S, Becker F, Yamamoto T, Scherer SW, Marshall CR, Walker S, Dutta UR, Dalal AB, Suckow V, Jamali P, Kahrizi K, Najmabadi H, Minassian BA.

Neurol Genet. 2017 Jun;3(3):e148. doi: 10.1212/NXG.0000000000000148.

PubMed [citation]

PMID:: 28589176
PMCID:: PMC5446782

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV002138878.3

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

Description

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg290 amino acid residue in ARHGEF9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25678704, 28589176). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 973141). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 29130122). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 290 of the ARHGEF9 protein (p.Arg290Cys).

#	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 7, 2024

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