VCV000973141.7 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 973141 Accession: VCV000973141.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq11.1 X: 63674094 (GRCh38) [ NCBI UCSC ] X: 62893974 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 19, 2020	May 1, 2024	Aug 16, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001353921.2:c.889C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001340850.1:p.Arg297Cys	missense
NM_001173479.2:c.709C>T	NP_001166950.1:p.Arg237Cys	missense
NM_001173480.2:c.562C>T	NP_001166951.1:p.Arg188Cys	missense
NM_001330495.2:c.805C>T	NP_001317424.1:p.Arg269Cys	missense
NM_001353922.2:c.889C>T	NP_001340851.1:p.Arg297Cys	missense
NM_001353923.1:c.907C>T	NP_001340852.1:p.Arg303Cys	missense
NM_001353924.2:c.688C>T	NP_001340853.1:p.Arg230Cys	missense
NM_001353926.2:c.688C>T	NP_001340855.1:p.Arg230Cys	missense
NM_001353927.2:c.805C>T	NP_001340856.1:p.Arg269Cys	missense
NM_001353928.2:c.868C>T	NP_001340857.1:p.Arg290Cys	missense
NM_001369030.1:c.868C>T	NP_001355959.1:p.Arg290Cys	missense
NM_001369031.1:c.868C>T	NP_001355960.1:p.Arg290Cys	missense
NM_001369032.1:c.868C>T	NP_001355961.1:p.Arg290Cys	missense
NM_001369033.1:c.805C>T	NP_001355962.1:p.Arg269Cys	missense
NM_001369034.1:c.805C>T	NP_001355963.1:p.Arg269Cys	missense
NM_001369035.1:c.805C>T	NP_001355964.1:p.Arg269Cys	missense
NM_001369036.1:c.805C>T	NP_001355965.1:p.Arg269Cys	missense
NM_001369037.1:c.805C>T	NP_001355966.1:p.Arg269Cys	missense
NM_001369038.1:c.805C>T	NP_001355967.1:p.Arg269Cys	missense
NM_001369039.1:c.688C>T	NP_001355968.1:p.Arg230Cys	missense
NM_001369040.1:c.688C>T	NP_001355969.1:p.Arg230Cys	missense
NM_001369041.1:c.805C>T	NP_001355970.1:p.Arg269Cys	missense
NM_001369042.1:c.562C>T	NP_001355971.1:p.Arg188Cys	missense
NM_001369043.1:c.805C>T	NP_001355972.1:p.Arg269Cys	missense
NM_001369044.1:c.805C>T	NP_001355973.1:p.Arg269Cys	missense
NM_001369045.1:c.454C>T	NP_001355974.1:p.Arg152Cys	missense
NM_015185.3:c.868C>T	NP_056000.1:p.Arg290Cys	missense
NC_000023.11:g.63674094G>A
NC_000023.10:g.62893974G>A
NG_016975.1:g.116453C>T

... more HGVS ... less HGVS

Protein change

R290C, R152C, R269C, R188C, R230C, R237C, R303C, R297C

Other names

Canonical SPDI

NC_000023.11:63674093:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs2050115619 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ARHGEF9		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	443	576

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autism spectrum disorder	Uncertain significance (1)	no assertion criteria provided	Dec 1, 2017	RCV001249523.2
Developmental and epileptic encephalopathy, 8	Uncertain significance (1)	criteria provided, single submitter	Aug 16, 2022	RCV001879754.4
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Mar 7, 2018	RCV002447235.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Aug 16, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Developmental and epileptic encephalopathy, 8 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002138878.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 25678704‚ 28589176‚ 29130122 Comment: 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 … (more) 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). (less)
Likely pathogenic (Mar 07, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002682177.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 29130122 Comment: The p.R290C variant (also known as c.868C>T), located in coding exon 6 of the ARHGEF9 gene, results from a C to T substitution at nucleotide … (more) The p.R290C variant (also known as c.868C>T), located in coding exon 6 of the ARHGEF9 gene, results from a C to T substitution at nucleotide position 868. The arginine at codon 290 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration co-segregated with disease in one family with four male siblings who all had refractory epileptic encephalopathy and carried this alteration. The alteration was determined to be inherited from the unaffected mother (Wang JY et al. Neurogenetics, 2018 Jan;19:9-16). Internal structural analysis indicates that this alteration is structurally deleterious (Ambry internal data; Xiang S et al. J. Mol. Biol., 2006 May;359:35-46). A different alteration located at the same position, p.R290H (c.869G>A), was identified in a male with seizures and intellectual disability (Lemke JR et al. Epilepsia, 2012 Aug;53:1387-98). The p.R290H variant was shown to impair proper function of the ARHGEF9 protein (Papadopoulos T et al. J. Biol. Chem., 2015 Mar;290:8256-70; Long P et al. Front Mol Neurosci, 2015 Jan;8:83). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Uncertain significance (Dec 01, 2017)	no assertion criteria provided Method: clinical testing	Autism spectrum disorder Affected status: yes Allele origin: unknown	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV001423513.1 First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 Comment: MOI : XL. . Missense	Sex: male Tissue: blood Method: targeted capture

Comment:

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).

Comment:

The p.R290C variant (also known as c.868C>T), located in coding exon 6 of the ARHGEF9 gene, results from a C to T substitution at nucleotide position 868. The arginine at codon 290 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration co-segregated with disease in one family with four male siblings who all had refractory epileptic encephalopathy and carried this alteration. The alteration was determined to be inherited from the unaffected mother (Wang JY et al. Neurogenetics, 2018 Jan;19:9-16). Internal structural analysis indicates that this alteration is structurally deleterious (Ambry internal data; Xiang S et al. J. Mol. Biol., 2006 May;359:35-46). A different alteration located at the same position, p.R290H (c.869G>A), was identified in a male with seizures and intellectual disability (Lemke JR et al. Epilepsia, 2012 Aug;53:1387-98). The p.R290H variant was shown to impair proper function of the ARHGEF9 protein (Papadopoulos T et al. J. Biol. Chem., 2015 Mar;290:8256-70; Long P et al. Front Mol Neurosci, 2015 Jan;8:83). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation.	Wang JY	Neurogenetics	2018	PMID: 29130122
ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation.	Alber M	Neurology. Genetics	2017	PMID: 28589176
Lipid binding defects and perturbed synaptogenic activity of a Collybistin R290H mutant that causes epilepsy and intellectual disability.	Papadopoulos T	The Journal of biological chemistry	2015	PMID: 25678704

Text-mined citations for rs2050115619 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2050115619 ...