NM_002576.5(PAK1):c.1225G>A (p.Gly409Arg) AND Inborn genetic diseases

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 29, 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:: RCV001266426.4

Allele description [Variation Report for NM_002576.5(PAK1):c.1225G>A (p.Gly409Arg)]

NM_002576.5(PAK1):c.1225G>A (p.Gly409Arg)

Gene:

PAK1:p21 (RAC1) activated kinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.5

Genomic location:

Preferred name:

NM_002576.5(PAK1):c.1225G>A (p.Gly409Arg)

HGVS:

NC_000011.10:g.77336274C>T
NG_029900.2:g.142790G>A
NM_001128620.2:c.1225G>A
NM_001376268.1:c.1225G>A
NM_001376269.1:c.1225G>A
NM_001376270.1:c.1225G>A
NM_001376271.1:c.1225G>A
NM_001376272.1:c.1246G>A
NM_001376273.1:c.1225G>A
NM_001376274.1:c.1225G>A
NM_001376275.1:c.1225G>A
NM_001376276.1:c.1225G>A
NM_001376277.1:c.1225G>A
NM_001376278.1:c.1225G>A
NM_001376279.1:c.1225G>A
NM_001376280.1:c.1225G>A
NM_001376281.1:c.1225G>A
NM_001376282.1:c.1225G>A
NM_001376283.1:c.1225G>A
NM_001376284.1:c.1225G>A
NM_001376285.1:c.1225G>A
NM_001376286.1:c.1225G>A
NM_001376287.1:c.1225G>A
NM_001376288.1:c.1225G>A
NM_001376289.1:c.1225G>A
NM_001376290.1:c.1117-15G>A
NM_001376291.1:c.1117-15G>A
NM_001376292.1:c.1225G>A
NM_001376293.1:c.1225G>A
NM_001376294.1:c.1216G>A
NM_001376295.1:c.1048G>A
NM_001376301.1:c.976G>A
NM_001376302.1:c.931G>A
NM_001376303.1:c.937G>A
NM_001376304.1:c.931G>A
NM_001376305.1:c.931G>A
NM_002576.5:c.1225G>AMANE SELECT
NP_001122092.1:p.Gly409Arg
NP_001363197.1:p.Gly409Arg
NP_001363198.1:p.Gly409Arg
NP_001363199.1:p.Gly409Arg
NP_001363200.1:p.Gly409Arg
NP_001363201.1:p.Gly416Arg
NP_001363202.1:p.Gly409Arg
NP_001363203.1:p.Gly409Arg
NP_001363204.1:p.Gly409Arg
NP_001363205.1:p.Gly409Arg
NP_001363206.1:p.Gly409Arg
NP_001363207.1:p.Gly409Arg
NP_001363208.1:p.Gly409Arg
NP_001363209.1:p.Gly409Arg
NP_001363210.1:p.Gly409Arg
NP_001363211.1:p.Gly409Arg
NP_001363212.1:p.Gly409Arg
NP_001363213.1:p.Gly409Arg
NP_001363214.1:p.Gly409Arg
NP_001363215.1:p.Gly409Arg
NP_001363216.1:p.Gly409Arg
NP_001363217.1:p.Gly409Arg
NP_001363218.1:p.Gly409Arg
NP_001363221.1:p.Gly409Arg
NP_001363222.1:p.Gly409Arg
NP_001363223.1:p.Gly406Arg
NP_001363224.1:p.Gly350Arg
NP_001363230.1:p.Gly326Arg
NP_001363231.1:p.Gly311Arg
NP_001363232.1:p.Gly313Arg
NP_001363233.1:p.Gly311Arg
NP_001363234.1:p.Gly311Arg
NP_002567.3:p.Gly409Arg
NC_000011.9:g.77047319C>T
NG_029900.1:g.142790G>A
NM_001128620.1:c.1225G>A
NR_164797.1:n.1441G>A
NR_164798.1:n.1444G>A

Protein change:

G311R

Links:

dbSNP: rs1942667410

NCBI 1000 Genomes Browser:

rs1942667410

Molecular consequence:

NM_001376290.1:c.1117-15G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001376291.1:c.1117-15G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001128620.2:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376268.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376269.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376270.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376271.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376272.1:c.1246G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376273.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376274.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376275.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376276.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376277.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376278.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376279.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376280.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376281.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376282.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376283.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376284.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376285.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376286.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376287.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376288.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376289.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376292.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376293.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376294.1:c.1216G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376295.1:c.1048G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376301.1:c.976G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376302.1:c.931G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376303.1:c.937G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376304.1:c.931G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376305.1:c.931G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002576.5:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_164797.1:n.1441G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_164798.1:n.1444G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001444600	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 29, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10975528, 30290153 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001444600

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 29, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch.

Lei M, Lu W, Meng W, Parrini MC, Eck MJ, Mayer BJ, Harrison SC.

Cell. 2000 Aug 4;102(3):387-97.

PubMed [citation]

PMID:: 10975528

Activating Mutations in PAK1, Encoding p21-Activated Kinase 1, Cause a Neurodevelopmental Disorder.

Harms FL, Kloth K, Bley A, Denecke J, Santer R, Lessel D, Hempel M, Kutsche K.

Am J Hum Genet. 2018 Oct 4;103(4):579-591. doi: 10.1016/j.ajhg.2018.09.005.

PubMed [citation]

PMID:: 30290153
PMCID:: PMC6174322

Details of each submission

From Ambry Genetics, SCV001444600.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.1225G>A (p.G409R) alteration is located in exon 13 (coding exon 12) of the PAK1 gene. This alteration results from a G to A substitution at nucleotide position 1225, causing the glycine (G) at amino acid position 409 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. The p.G409 amino acid is located within the activation loop in the kinase catalytic core (Lei, 2000). PAK1 exists as an autoinhibited homodimer until its kinase activity is activated by binding to the GTP-bound forms of Rho GTPases, CDC42 and RAC1 (reviewed in Harms, 2018). The activation loop is bound by the N-terminal kinase inhibitory (KI) segment in the autoinhibited conformation of the PAK1 dimer. Upon binding of the dimer to CDC42 or RAC1, a conformational change releases the activation loop from the KI segment followed by phosphorylation to activate the PAK1 kinase enzyme (Lei, 2000). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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

Last Updated: May 1, 2024

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