VCV000931474.15 - ClinVar

NM_001353921.2(ARHGEF9):c.652C>G (p.Leu218Val)

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.

(5)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001353921.2(ARHGEF9):c.652C>G (p.Leu218Val)

Variation ID: 931474 Accession: VCV000931474.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq11.1 X: 63678503 (GRCh38) [ NCBI UCSC ] X: 62898383 (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 4, 2020	Oct 8, 2024	Dec 13, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001353921.2:c.652C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001340850.1:p.Leu218Val	missense
NM_001173479.2:c.472C>G	NP_001166950.1:p.Leu158Val	missense
NM_001173480.2:c.325C>G	NP_001166951.1:p.Leu109Val	missense
NM_001330495.2:c.568C>G	NP_001317424.1:p.Leu190Val	missense
NM_001353922.2:c.652C>G	NP_001340851.1:p.Leu218Val	missense
NM_001353923.1:c.670C>G	NP_001340852.1:p.Leu224Val	missense
NM_001353924.2:c.451C>G	NP_001340853.1:p.Leu151Val	missense
NM_001353926.2:c.451C>G	NP_001340855.1:p.Leu151Val	missense
NM_001353927.2:c.568C>G	NP_001340856.1:p.Leu190Val	missense
NM_001353928.2:c.631C>G	NP_001340857.1:p.Leu211Val	missense
NM_001369030.1:c.631C>G	NP_001355959.1:p.Leu211Val	missense
NM_001369031.1:c.631C>G	NP_001355960.1:p.Leu211Val	missense
NM_001369032.1:c.631C>G	NP_001355961.1:p.Leu211Val	missense
NM_001369033.1:c.568C>G	NP_001355962.1:p.Leu190Val	missense
NM_001369034.1:c.568C>G	NP_001355963.1:p.Leu190Val	missense
NM_001369035.1:c.568C>G	NP_001355964.1:p.Leu190Val	missense
NM_001369036.1:c.568C>G	NP_001355965.1:p.Leu190Val	missense
NM_001369037.1:c.568C>G	NP_001355966.1:p.Leu190Val	missense
NM_001369038.1:c.568C>G	NP_001355967.1:p.Leu190Val	missense
NM_001369039.1:c.451C>G	NP_001355968.1:p.Leu151Val	missense
NM_001369040.1:c.451C>G	NP_001355969.1:p.Leu151Val	missense
NM_001369041.1:c.568C>G	NP_001355970.1:p.Leu190Val	missense
NM_001369042.1:c.325C>G	NP_001355971.1:p.Leu109Val	missense
NM_001369043.1:c.568C>G	NP_001355972.1:p.Leu190Val	missense
NM_001369044.1:c.568C>G	NP_001355973.1:p.Leu190Val	missense
NM_001369045.1:c.217C>G	NP_001355974.1:p.Leu73Val	missense
NM_015185.3:c.631C>G	NP_056000.1:p.Leu211Val	missense
NC_000023.11:g.63678503G>C
NC_000023.10:g.62898383G>C
NG_016975.1:g.112044C>G

... more HGVS ... less HGVS

Protein change

L73V, L211V, L224V, L109V, L151V, L190V, L218V, L158V

Other names

Canonical SPDI

NC_000023.11:63678502:G:C

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: rs2050412325 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	445	578

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.
Developmental and epileptic encephalopathy, 8	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Dec 13, 2022	RCV001198047.10
not provided	Uncertain significance (1)	criteria provided, single submitter	May 10, 2019	RCV001569841.3
ARHGEF9-related disorder	Uncertain significance (1)	no assertion criteria provided	Jan 2, 2024	RCV004548051.2

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 (Apr 03, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 8 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368832.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in … (more) This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3. This variant was detected in hemizygous state. (less)
Uncertain significance (May 10, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001793998.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Comment: Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has … (more) Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge (less)
Uncertain significance (Oct 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 8 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580417.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PM2_SUP	Number of individuals with the variant: 1 Sex: male
Uncertain significance (Dec 13, 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: SCV002156388.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Comment: 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) … (more) 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. ClinVar contains an entry for this variant (Variation ID: 931474). This variant has not been reported in the literature in individuals affected with ARHGEF9-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 211 of the ARHGEF9 protein (p.Leu211Val). 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. (less)
Uncertain significance (Jan 02, 2024)	no assertion criteria provided Method: clinical testing	ARHGEF9-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004716400.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The ARHGEF9 c.631C>G variant is predicted to result in the amino acid substitution p.Leu211Val. To our knowledge, this variant has not been reported in the … (more) The ARHGEF9 c.631C>G variant is predicted to result in the amino acid substitution p.Leu211Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3. This variant was detected in hemizygous state.

Comment:

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge

Comment:

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. ClinVar contains an entry for this variant (Variation ID: 931474). This variant has not been reported in the literature in individuals affected with ARHGEF9-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 211 of the ARHGEF9 protein (p.Leu211Val). 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.

Comment:

The ARHGEF9 c.631C>G variant is predicted to result in the amino acid substitution p.Leu211Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs2050412325 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001353921.2(ARHGEF9):c.652C>G (p.Leu218Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2050412325 ...