NM_001353921.2(ARHGEF9):c.442A>G (p.Ser148Gly) AND Developmental and epileptic encephalopathy, 8

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 31, 2018
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:: RCV000686743.9

Allele description [Variation Report for NM_001353921.2(ARHGEF9):c.442A>G (p.Ser148Gly)]

NM_001353921.2(ARHGEF9):c.442A>G (p.Ser148Gly)

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.442A>G (p.Ser148Gly)

HGVS:

NC_000023.11:g.63697265T>C
NG_016975.1:g.93282A>G
NM_001173479.2:c.262A>G
NM_001173480.2:c.115A>G
NM_001330495.2:c.358A>G
NM_001353921.2:c.442A>GMANE SELECT
NM_001353922.2:c.442A>G
NM_001353923.1:c.460A>G
NM_001353924.2:c.241A>G
NM_001353926.2:c.241A>G
NM_001353927.2:c.358A>G
NM_001353928.2:c.421A>G
NM_001369030.1:c.421A>G
NM_001369031.1:c.421A>G
NM_001369032.1:c.421A>G
NM_001369033.1:c.358A>G
NM_001369034.1:c.358A>G
NM_001369035.1:c.358A>G
NM_001369036.1:c.358A>G
NM_001369037.1:c.358A>G
NM_001369038.1:c.358A>G
NM_001369039.1:c.241A>G
NM_001369040.1:c.241A>G
NM_001369041.1:c.358A>G
NM_001369042.1:c.115A>G
NM_001369043.1:c.358A>G
NM_001369044.1:c.358A>G
NM_001369045.1:c.7A>G
NM_015185.3:c.421A>G
NP_001166950.1:p.Ser88Gly
NP_001166951.1:p.Ser39Gly
NP_001317424.1:p.Ser120Gly
NP_001340850.1:p.Ser148Gly
NP_001340851.1:p.Ser148Gly
NP_001340852.1:p.Ser154Gly
NP_001340853.1:p.Ser81Gly
NP_001340855.1:p.Ser81Gly
NP_001340856.1:p.Ser120Gly
NP_001340857.1:p.Ser141Gly
NP_001355959.1:p.Ser141Gly
NP_001355960.1:p.Ser141Gly
NP_001355961.1:p.Ser141Gly
NP_001355962.1:p.Ser120Gly
NP_001355963.1:p.Ser120Gly
NP_001355964.1:p.Ser120Gly
NP_001355965.1:p.Ser120Gly
NP_001355966.1:p.Ser120Gly
NP_001355967.1:p.Ser120Gly
NP_001355968.1:p.Ser81Gly
NP_001355969.1:p.Ser81Gly
NP_001355970.1:p.Ser120Gly
NP_001355971.1:p.Ser39Gly
NP_001355972.1:p.Ser120Gly
NP_001355973.1:p.Ser120Gly
NP_001355974.1:p.Ser3Gly
NP_056000.1:p.Ser141Gly
NC_000023.10:g.62917145T>C
NM_015185.2:c.421A>G

Protein change:

S120G

Links:

dbSNP: rs1394345886

NCBI 1000 Genomes Browser:

rs1394345886

Molecular consequence:

NM_001173479.2:c.262A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001173480.2:c.115A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330495.2:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353921.2:c.442A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353922.2:c.442A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353923.1:c.460A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353924.2:c.241A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353926.2:c.241A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353927.2:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001353928.2:c.421A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369030.1:c.421A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369031.1:c.421A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369032.1:c.421A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369033.1:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369034.1:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369035.1:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369036.1:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369037.1:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369038.1:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369039.1:c.241A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369040.1:c.241A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369041.1:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369042.1:c.115A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369043.1:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369044.1:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369045.1:c.7A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_015185.3:c.421A>G - 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
SCV000814275	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 29, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000897578	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000814275

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 29, 2018)

germline

clinical testing

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

SCV000897578

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 31, 2018)

unknown

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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

PMC

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.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000814275.4

#	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. 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: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ARHGEF9-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with glycine at codon 141 of the ARHGEF9 protein (p.Ser141Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine.

#	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

From Fulgent Genetics, Fulgent Genetics, SCV000897578.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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