NM_006908.5(RAC1):c.191A>G (p.Tyr64Cys) AND Intellectual disability, autosomal dominant 48

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 3, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001808906.4

Allele description [Variation Report for NM_006908.5(RAC1):c.191A>G (p.Tyr64Cys)]

NM_006908.5(RAC1):c.191A>G (p.Tyr64Cys)

Gene:

RAC1:Rac family small GTPase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p22.1

Genomic location:

Preferred name:

NM_006908.5(RAC1):c.191A>G (p.Tyr64Cys)

HGVS:

NC_000007.14:g.6392007A>G
NG_029431.1:g.22513A>G
NM_006908.5:c.191A>GMANE SELECT
NM_018890.4:c.191A>G
NP_008839.2:p.Tyr64Cys
NP_061485.1:p.Tyr64Cys
NC_000007.13:g.6431638A>G
NM_006908.4:c.191A>G

Protein change:

Y64C; TYR64CYS

Links:

OMIM: 602048.0008; dbSNP: rs2115201389

NCBI 1000 Genomes Browser:

rs2115201389

Molecular consequence:

NM_006908.5:c.191A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_018890.4:c.191A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Intellectual disability, autosomal dominant 48
Synonyms:: MENTAL RETARDATION, AUTOSOMAL DOMINANT 48; INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 48
Identifiers:: MONDO: MONDO:0030913; MedGen: C4540321; OMIM: 617751

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002059157	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003845961	OMIM	no assertion criteria provided	Pathogenic (Mar 30, 2023)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002059157

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 3, 2022)

germline

clinical testing

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

SCV003845961

OMIM

no assertion criteria provided

Pathogenic
(Mar 30, 2023)

germline

literature only

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

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

Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology.

Banka S, Bennington A, Baker MJ, Rijckmans E, Clemente GD, Ansor NM, Sito H, Prasad P, Anyane-Yeboa K, Badalato L, Dimitrov B, Fitzpatrick D, Hurst ACE, Jansen AC, Kelly MA, Krantz I, Rieubland C, Ross M, Rudy NL, Sanz J, Stouffs K, Xu ZL, et al.

Brain. 2022 Dec 19;145(12):4232-4245. doi: 10.1093/brain/awac049.

PubMed [citation]

PMID:: 35139179
PMCID:: PMC9762944

Details of each submission

From 3billion, SCV002059157.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000445283, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.902, 3CNET: 0.881, PP3_P). A missense variant is a common mechanism associated with Mental retardation (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From OMIM, SCV003845961.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 3-year-old girl (patient 6) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751), Banka et al. (2022) identified heterozygosity for a c.191A-G transition (c.191A-G, NM_006908.4) in the RAC1 gene, resulting in a tyr64-to-cys (Y64C) 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. Expression of RAC1 with the Y64C mutation in NIH3T3 fibroblasts resulted in increased signaling through the WAVE regulatory complex (WRC) and PAK family kinases.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2025

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