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NM_001353921.2(ARHGEF9):c.1033C>T (p.Arg345Trp) AND Developmental and epileptic encephalopathy, 8

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 16, 2023
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:
RCV001040965.8

Allele description [Variation Report for NM_001353921.2(ARHGEF9):c.1033C>T (p.Arg345Trp)]

NM_001353921.2(ARHGEF9):c.1033C>T (p.Arg345Trp)

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.1033C>T (p.Arg345Trp)
HGVS:
  • NC_000023.11:g.63665930G>A
  • NG_016975.1:g.124617C>T
  • NM_001173479.2:c.853C>T
  • NM_001173480.2:c.706C>T
  • NM_001330495.2:c.949C>T
  • NM_001353921.2:c.1033C>TMANE SELECT
  • NM_001353922.2:c.945+8108C>T
  • NM_001353923.1:c.1051C>T
  • NM_001353924.2:c.832C>T
  • NM_001353926.2:c.832C>T
  • NM_001353927.2:c.861+8108C>T
  • NM_001353928.2:c.924+8108C>T
  • NM_001369030.1:c.1012C>T
  • NM_001369031.1:c.1012C>T
  • NM_001369032.1:c.1012C>T
  • NM_001369033.1:c.949C>T
  • NM_001369034.1:c.949C>T
  • NM_001369035.1:c.949C>T
  • NM_001369036.1:c.949C>T
  • NM_001369037.1:c.949C>T
  • NM_001369038.1:c.949C>T
  • NM_001369039.1:c.832C>T
  • NM_001369040.1:c.832C>T
  • NM_001369041.1:c.861+8108C>T
  • NM_001369042.1:c.706C>T
  • NM_001369043.1:c.949C>T
  • NM_001369044.1:c.949C>T
  • NM_001369045.1:c.510+8108C>T
  • NM_015185.3:c.1012C>T
  • NP_001166950.1:p.Arg285Trp
  • NP_001166951.1:p.Arg236Trp
  • NP_001317424.1:p.Arg317Trp
  • NP_001340850.1:p.Arg345Trp
  • NP_001340852.1:p.Arg351Trp
  • NP_001340853.1:p.Arg278Trp
  • NP_001340855.1:p.Arg278Trp
  • NP_001355959.1:p.Arg338Trp
  • NP_001355960.1:p.Arg338Trp
  • NP_001355961.1:p.Arg338Trp
  • NP_001355962.1:p.Arg317Trp
  • NP_001355963.1:p.Arg317Trp
  • NP_001355964.1:p.Arg317Trp
  • NP_001355965.1:p.Arg317Trp
  • NP_001355966.1:p.Arg317Trp
  • NP_001355967.1:p.Arg317Trp
  • NP_001355968.1:p.Arg278Trp
  • NP_001355969.1:p.Arg278Trp
  • NP_001355971.1:p.Arg236Trp
  • NP_001355972.1:p.Arg317Trp
  • NP_001355973.1:p.Arg317Trp
  • NP_056000.1:p.Arg338Trp
  • NC_000023.10:g.62885810G>A
  • NM_015185.2:c.1012C>T
Protein change:
R236W
Links:
dbSNP: rs869312941
NCBI 1000 Genomes Browser:
rs869312941
Molecular consequence:
  • NM_001353922.2:c.945+8108C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001353927.2:c.861+8108C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001353928.2:c.924+8108C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001369041.1:c.861+8108C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001369045.1:c.510+8108C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001173479.2:c.853C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173480.2:c.706C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330495.2:c.949C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353921.2:c.1033C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353923.1:c.1051C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353924.2:c.832C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001353926.2:c.832C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369030.1:c.1012C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369031.1:c.1012C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369032.1:c.1012C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369033.1:c.949C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369034.1:c.949C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369035.1:c.949C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369036.1:c.949C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369037.1:c.949C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369038.1:c.949C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369039.1:c.832C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369040.1:c.832C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369042.1:c.706C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369043.1:c.949C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369044.1:c.949C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015185.3:c.1012C>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001204558Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Oct 16, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism.

Long P, May MM, James VM, Grannò S, Johnson JP, Tarpey P, Stevenson RE, Harvey K, Schwartz CE, Harvey RJ.

Front Mol Neurosci. 2015;8:83. doi: 10.3389/fnmol.2015.00083.

PubMed [citation]
PMID:
26834553
PMCID:
PMC4719118

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001204558.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 338 of the ARHGEF9 protein (p.Arg338Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with syndromic X-linked intellectual disability or epileptic encephalopathy (PMID: 26834553; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225050). 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 ARHGEF9 protein function. Experimental studies have shown that this missense change affects ARHGEF9 function (PMID: 26834553). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2024