NM_001353921.2(ARHGEF9):c.331C>T (p.Arg111Trp) AND Developmental and epileptic encephalopathy, 8

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jul 31, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV001004681.10

Allele description [Variation Report for NM_001353921.2(ARHGEF9):c.331C>T (p.Arg111Trp)]

NM_001353921.2(ARHGEF9):c.331C>T (p.Arg111Trp)

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.331C>T (p.Arg111Trp)

HGVS:

NC_000023.11:g.63706329G>A
NG_016975.1:g.84218C>T
NM_001173479.2:c.151C>T
NM_001173480.2:c.4C>T
NM_001330495.2:c.247C>T
NM_001353921.2:c.331C>TMANE SELECT
NM_001353922.2:c.331C>T
NM_001353923.1:c.349C>T
NM_001353924.2:c.130C>T
NM_001353926.2:c.130C>T
NM_001353927.2:c.247C>T
NM_001353928.2:c.310C>T
NM_001369030.1:c.310C>T
NM_001369031.1:c.310C>T
NM_001369032.1:c.310C>T
NM_001369033.1:c.247C>T
NM_001369034.1:c.247C>T
NM_001369035.1:c.247C>T
NM_001369036.1:c.247C>T
NM_001369037.1:c.247C>T
NM_001369038.1:c.247C>T
NM_001369039.1:c.130C>T
NM_001369040.1:c.130C>T
NM_001369041.1:c.247C>T
NM_001369042.1:c.4C>T
NM_001369043.1:c.247C>T
NM_001369044.1:c.247C>T
NM_001369045.1:c.-373C>T
NM_015185.3:c.310C>T
NP_001166950.1:p.Arg51Trp
NP_001166951.1:p.Arg2Trp
NP_001317424.1:p.Arg83Trp
NP_001340850.1:p.Arg111Trp
NP_001340851.1:p.Arg111Trp
NP_001340852.1:p.Arg117Trp
NP_001340853.1:p.Arg44Trp
NP_001340855.1:p.Arg44Trp
NP_001340856.1:p.Arg83Trp
NP_001340857.1:p.Arg104Trp
NP_001355959.1:p.Arg104Trp
NP_001355960.1:p.Arg104Trp
NP_001355961.1:p.Arg104Trp
NP_001355962.1:p.Arg83Trp
NP_001355963.1:p.Arg83Trp
NP_001355964.1:p.Arg83Trp
NP_001355965.1:p.Arg83Trp
NP_001355966.1:p.Arg83Trp
NP_001355967.1:p.Arg83Trp
NP_001355968.1:p.Arg44Trp
NP_001355969.1:p.Arg44Trp
NP_001355970.1:p.Arg83Trp
NP_001355971.1:p.Arg2Trp
NP_001355972.1:p.Arg83Trp
NP_001355973.1:p.Arg83Trp
NP_056000.1:p.Arg104Trp
NC_000023.10:g.62926209G>A
NM_015185.2:c.310C>T
p.Arg104Trp

Protein change:

R104W

Links:

Molecular consequence:

NM_001369045.1:c.-373C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001173479.2:c.151C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173480.2:c.4C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330495.2:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353921.2:c.331C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353922.2:c.331C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353923.1:c.349C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353924.2:c.130C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353926.2:c.130C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353927.2:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001353928.2:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369030.1:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369031.1:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369032.1:c.310C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369033.1:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369034.1:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369035.1:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369036.1:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369037.1:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369038.1:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369039.1:c.130C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369040.1:c.130C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369041.1:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369042.1:c.4C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369043.1:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369044.1:c.247C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_015185.3:c.310C>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
SCV001164137	Génétique des Maladies du Développement, Hospices Civils de Lyon	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 16, 2018)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001245204	Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 14, 2020)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001760522	Genomics England Pilot Project, Genomics England	no assertion criteria provided (ACGS Guidelines, 2016)	Likely pathogenic	germline	clinical testing	Citation Link,
SCV002260931	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 31, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	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

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 Génétique des Maladies du Développement, Hospices Civils de Lyon, SCV001164137.1

#	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	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics, SCV001245204.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomics England Pilot Project, Genomics England, SCV001760522.1

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002260931.3

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

Description

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. 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) performed at Invitae indicates that this missense variant is expected to disrupt ARHGEF9 protein function. ClinVar contains an entry for this variant (Variation ID: 501568). This variant has not been reported in the literature in individuals affected with ARHGEF9-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 104 of the ARHGEF9 protein (p.Arg104Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan.

#	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: Sep 29, 2024

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