VCV001098331.7 - ClinVar

NM_006908.5(RAC1):c.218C>T (p.Pro73Leu)

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.

(4)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006908.5(RAC1):c.218C>T (p.Pro73Leu)

Variation ID: 1098331 Accession: VCV001098331.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.1 7: 6392034 (GRCh38) [ NCBI UCSC ] 7: 6431665 (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	May 20, 2021	Feb 14, 2024	May 4, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_006908.5:c.218C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_008839.2:p.Pro73Leu	missense
NM_018890.4:c.218C>T	NP_061485.1:p.Pro73Leu	missense
NC_000007.14:g.6392034C>T
NC_000007.13:g.6431665C>T
NG_029431.1:g.22540C>T

... more HGVS ... less HGVS

Protein change

P73L

Other names

Canonical SPDI

NC_000007.14:6392033:C:T

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: rs2115201441 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	63	126

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.
See cases	Likely pathogenic (1)	criteria provided, single submitter	Apr 26, 2021	RCV001420220.2
not provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 12, 2021	RCV001882529.6
Intellectual disability, autosomal dominant 48	Pathogenic (1)	criteria provided, single submitter	May 4, 2022	RCV002246381.1

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.
Likely pathogenic (Apr 26, 2021)	criteria provided, single submitter (Parc Tauli Hospital Assertion Criteria 2021) Method: clinical testing	See cases (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli Accession: SCV001622640.1 First in ClinVar: May 20, 2021 Last updated: May 20, 2021	Comment: PM2_supporting;PM6_moderate;PP5_moderate;PP2_supporting;PP3_supporting Clinical Features: Intellectual disability, mild (present) , Short tubular bones of the hand (present) , Attention deficit hyperactivity disorder (present) , Autism (present) , Specific learning disability … (more) Intellectual disability, mild (present) , Short tubular bones of the hand (present) , Attention deficit hyperactivity disorder (present) , Autism (present) , Specific learning disability (present) (less) Sex: male
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Intellectual disability, autosomal dominant 48 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002518957.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV002568829.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022
Likely pathogenic (Nov 12, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002296137.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28886345 Comment: Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RAC1 function (PMID: 28886345). Algorithms developed to predict the … (more) Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RAC1 function (PMID: 28886345). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1098331). This missense change has been observed in individual(s) with RAC1-related conditions (PMID: 28886345). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 73 of the RAC1 protein (p.Pro73Leu). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)

Comment:

Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RAC1 function (PMID: 28886345). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1098331). This missense change has been observed in individual(s) with RAC1-related conditions (PMID: 28886345). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 73 of the RAC1 protein (p.Pro73Leu). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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
RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes.	Reijnders MRF	American journal of human genetics	2017	PMID: 28886345

Text-mined citations for rs2115201441 ...

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_006908.5(RAC1):c.218C>T (p.Pro73Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2115201441 ...