VCV002446363.2 - ClinVar

NM_006908.5(RAC1):c.181C>G (p.Gln61Glu)

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.

(2)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006908.5(RAC1):c.181C>G (p.Gln61Glu)

Variation ID: 2446363 Accession: VCV002446363.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.1 7: 6391997 (GRCh38) [ NCBI UCSC ] 7: 6431628 (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	Apr 2, 2023	Oct 7, 2023	Sep 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006908.5:c.181C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_008839.2:p.Gln61Glu	missense
NM_018890.3:c.181C>G
NM_018890.4:c.181C>G	NP_061485.1:p.Gln61Glu	missense
NC_000007.14:g.6391997C>G
NC_000007.13:g.6431628C>G
NG_029431.1:g.22503C>G

... more HGVS ... less HGVS

Protein change

Q61E

Other names

Canonical SPDI

NC_000007.14:6391996:C:G

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

OMIM: 602048.0007 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.
RAC1		-	-	GRCh38 GRCh37	62	124

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.
Intellectual disability, autosomal dominant 48	Pathogenic (1)	no assertion criteria provided	Mar 28, 2023	RCV003156716.1
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 26, 2023	RCV003332418.1

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.
Pathogenic (Sep 26, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004040122.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Comment: Published functional studies have demonstrated the p.(Q61E) enhances nuclear accumulation (Sandrock et al., 2010) and alters GTP hydrolysis activity (Lerm et al., 1999); Not observed … (more) Published functional studies have demonstrated the p.(Q61E) enhances nuclear accumulation (Sandrock et al., 2010) and alters GTP hydrolysis activity (Lerm et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16088958, 29362425, 9916051, 15143066, 28317937, 10542213, 21824110, 35139179, 19961560) (less)
Pathogenic (Mar 28, 2023)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 48 Affected status: not provided Allele origin: germline	OMIM Accession: SCV003845960.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023	Publications: PubMed (1) PubMed: 35139179 Comment on evidence: In a 2-year-old girl (patient 1) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751), Banka et al. (2022) identified heterozygosity for a c.181C-G transversion (c.181C-G, … (more) In a 2-year-old girl (patient 1) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751), Banka et al. (2022) identified heterozygosity for a c.181C-G transversion (c.181C-G, NM_006908.4) in the RAC1 gene, resulting in a gln61-to-glu (Q61E) substitution in the RAC1 switch II region. The mutation, which was identified as part of the Deciphering Developmental Disorders Study, was found to be de novo. (less)

Comment:

Published functional studies have demonstrated the p.(Q61E) enhances nuclear accumulation (Sandrock et al., 2010) and alters GTP hydrolysis activity (Lerm et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16088958, 29362425, 9916051, 15143066, 28317937, 10542213, 21824110, 35139179, 19961560)

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
Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology.	Banka S	Brain : a journal of neurology	2022	PMID: 35139179

Text-mined citations for this variant ...

Record last updated Oct 07, 2023

ClinVar Genomic variation as it relates to human health

NM_006908.5(RAC1):c.181C>G (p.Gln61Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...