NM_002576.5(PAK1):c.1409T>G (p.Leu470Arg) AND Intellectual developmental disorder with macrocephaly, seizures, and speech delay

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Nov 23, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001262617.4

Allele description [Variation Report for NM_002576.5(PAK1):c.1409T>G (p.Leu470Arg)]

NM_002576.5(PAK1):c.1409T>G (p.Leu470Arg)

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.1409T>G (p.Leu470Arg)

HGVS:

NC_000011.10:g.77336090A>C
NG_029900.2:g.142974T>G
NM_001128620.2:c.1409T>G
NM_001376268.1:c.1409T>G
NM_001376269.1:c.1409T>G
NM_001376270.1:c.1409T>G
NM_001376271.1:c.1409T>G
NM_001376272.1:c.1430T>G
NM_001376273.1:c.1409T>G
NM_001376274.1:c.1409T>G
NM_001376275.1:c.1409T>G
NM_001376276.1:c.1409T>G
NM_001376277.1:c.1409T>G
NM_001376278.1:c.1409T>G
NM_001376279.1:c.1409T>G
NM_001376280.1:c.1409T>G
NM_001376281.1:c.1409T>G
NM_001376282.1:c.1409T>G
NM_001376283.1:c.1409T>G
NM_001376284.1:c.1409T>G
NM_001376285.1:c.1409T>G
NM_001376286.1:c.1409T>G
NM_001376287.1:c.1409T>G
NM_001376288.1:c.1409T>G
NM_001376289.1:c.1409T>G
NM_001376290.1:c.1286T>G
NM_001376291.1:c.1286T>G
NM_001376292.1:c.1409T>G
NM_001376293.1:c.1409T>G
NM_001376294.1:c.1400T>G
NM_001376295.1:c.1232T>G
NM_001376301.1:c.1160T>G
NM_001376302.1:c.1115T>G
NM_001376303.1:c.1121T>G
NM_001376304.1:c.1115T>G
NM_001376305.1:c.1115T>G
NM_002576.5:c.1409T>GMANE SELECT
NP_001122092.1:p.Leu470Arg
NP_001363197.1:p.Leu470Arg
NP_001363198.1:p.Leu470Arg
NP_001363199.1:p.Leu470Arg
NP_001363200.1:p.Leu470Arg
NP_001363201.1:p.Leu477Arg
NP_001363202.1:p.Leu470Arg
NP_001363203.1:p.Leu470Arg
NP_001363204.1:p.Leu470Arg
NP_001363205.1:p.Leu470Arg
NP_001363206.1:p.Leu470Arg
NP_001363207.1:p.Leu470Arg
NP_001363208.1:p.Leu470Arg
NP_001363209.1:p.Leu470Arg
NP_001363210.1:p.Leu470Arg
NP_001363211.1:p.Leu470Arg
NP_001363212.1:p.Leu470Arg
NP_001363213.1:p.Leu470Arg
NP_001363214.1:p.Leu470Arg
NP_001363215.1:p.Leu470Arg
NP_001363216.1:p.Leu470Arg
NP_001363217.1:p.Leu470Arg
NP_001363218.1:p.Leu470Arg
NP_001363219.1:p.Leu429Arg
NP_001363220.1:p.Leu429Arg
NP_001363221.1:p.Leu470Arg
NP_001363222.1:p.Leu470Arg
NP_001363223.1:p.Leu467Arg
NP_001363224.1:p.Leu411Arg
NP_001363230.1:p.Leu387Arg
NP_001363231.1:p.Leu372Arg
NP_001363232.1:p.Leu374Arg
NP_001363233.1:p.Leu372Arg
NP_001363234.1:p.Leu372Arg
NP_002567.3:p.Leu470Arg
NC_000011.9:g.77047135A>C
NG_029900.1:g.142974T>G
NM_001128620.1:c.1409T>G
NR_164797.1:n.1625T>G
NR_164798.1:n.1628T>G

Protein change:

L372R

Links:

dbSNP: rs1942648391

NCBI 1000 Genomes Browser:

rs1942648391

Molecular consequence:

NM_001128620.2:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376268.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376269.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376270.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376271.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376272.1:c.1430T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376273.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376274.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376275.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376276.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376277.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376278.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376279.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376280.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376281.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376282.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376283.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376284.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376285.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376286.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376287.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376288.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376289.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376290.1:c.1286T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376291.1:c.1286T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376292.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376293.1:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376294.1:c.1400T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376295.1:c.1232T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376301.1:c.1160T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376302.1:c.1115T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376303.1:c.1121T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376304.1:c.1115T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001376305.1:c.1115T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002576.5:c.1409T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_164797.1:n.1625T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_164798.1:n.1628T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Intellectual developmental disorder with macrocephaly, seizures, and speech delay
Identifiers:: MONDO: MONDO:0032568; MedGen: C4748428; OMIM: 618158

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bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 [Homo sapiens]
bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 [Homo sapiens]
gi|46094058|ref|NP_005434.4|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001440552	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 23, 2023)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001762361	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 9, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10975528, 30290153, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001440552

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 23, 2023)

de novo

clinical testing

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

SCV001762361

Johns Hopkins Genomics, Johns Hopkins University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 9, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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
not provided	de novo	yes	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

See all PubMed Citations (3)

Details of each submission

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440552.3

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

Description

Criteria applied: PS2_MOD,PM1,PM5,PS4_SUP,PM2_SUP,PP3; Re-Eval 23.11.2023 RoJ

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

From Johns Hopkins Genomics, Johns Hopkins University, SCV001762361.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This PAK1 variant is absent from a large population dataset and has not been reported in the literature, to our knowledge. It has an entry in ClinVar. Three bioinformatics tools queried predict that this substitution would be damaging, and the leucine residue at this position is conserved across all vertebrate species assessed. This leucine to arginine substitution is located in PAK1 kinase domain. The crystal structure of the human PAK1 protein shows this residue (Leu470) interacts with the inhibitory switch (IS) domain, which is required for autoinhibition of PAK1 kinase activity. This variant is not predicted to affect normal exon 13 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1409T>G to be likely pathogenic.

#	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: Dec 24, 2023

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