NM_002576.5(PAK1):c.391T>A (p.Tyr131Asn) AND Intellectual developmental disorder with macrocephaly, seizures, and speech delay

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 2, 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:: RCV001528115.3

Allele description [Variation Report for NM_002576.5(PAK1):c.391T>A (p.Tyr131Asn)]

NM_002576.5(PAK1):c.391T>A (p.Tyr131Asn)

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.391T>A (p.Tyr131Asn)

HGVS:

NC_000011.10:g.77379289A>T
NG_029900.2:g.99775T>A
NM_001128620.2:c.391T>A
NM_001376268.1:c.391T>A
NM_001376269.1:c.391T>A
NM_001376270.1:c.391T>A
NM_001376271.1:c.391T>A
NM_001376272.1:c.412T>A
NM_001376273.1:c.391T>A
NM_001376274.1:c.391T>A
NM_001376275.1:c.391T>A
NM_001376276.1:c.391T>A
NM_001376277.1:c.391T>A
NM_001376278.1:c.391T>A
NM_001376279.1:c.391T>A
NM_001376280.1:c.391T>A
NM_001376281.1:c.391T>A
NM_001376282.1:c.391T>A
NM_001376283.1:c.391T>A
NM_001376284.1:c.391T>A
NM_001376285.1:c.391T>A
NM_001376286.1:c.391T>A
NM_001376287.1:c.391T>A
NM_001376288.1:c.391T>A
NM_001376289.1:c.391T>A
NM_001376290.1:c.391T>A
NM_001376291.1:c.391T>A
NM_001376292.1:c.391T>A
NM_001376293.1:c.391T>A
NM_001376294.1:c.391T>A
NM_001376295.1:c.391T>A
NM_001376301.1:c.191-4924T>A
NM_001376302.1:c.97T>A
NM_001376303.1:c.391T>A
NM_001376304.1:c.97T>A
NM_001376305.1:c.97T>A
NM_002576.5:c.391T>AMANE SELECT
NP_001122092.1:p.Tyr131Asn
NP_001363197.1:p.Tyr131Asn
NP_001363198.1:p.Tyr131Asn
NP_001363199.1:p.Tyr131Asn
NP_001363200.1:p.Tyr131Asn
NP_001363201.1:p.Tyr138Asn
NP_001363202.1:p.Tyr131Asn
NP_001363203.1:p.Tyr131Asn
NP_001363204.1:p.Tyr131Asn
NP_001363205.1:p.Tyr131Asn
NP_001363206.1:p.Tyr131Asn
NP_001363207.1:p.Tyr131Asn
NP_001363208.1:p.Tyr131Asn
NP_001363209.1:p.Tyr131Asn
NP_001363210.1:p.Tyr131Asn
NP_001363211.1:p.Tyr131Asn
NP_001363212.1:p.Tyr131Asn
NP_001363213.1:p.Tyr131Asn
NP_001363214.1:p.Tyr131Asn
NP_001363215.1:p.Tyr131Asn
NP_001363216.1:p.Tyr131Asn
NP_001363217.1:p.Tyr131Asn
NP_001363218.1:p.Tyr131Asn
NP_001363219.1:p.Tyr131Asn
NP_001363220.1:p.Tyr131Asn
NP_001363221.1:p.Tyr131Asn
NP_001363222.1:p.Tyr131Asn
NP_001363223.1:p.Tyr131Asn
NP_001363224.1:p.Tyr131Asn
NP_001363231.1:p.Tyr33Asn
NP_001363232.1:p.Tyr131Asn
NP_001363233.1:p.Tyr33Asn
NP_001363234.1:p.Tyr33Asn
NP_002567.3:p.Tyr131Asn
NC_000011.9:g.77090334A>T
NM_002576.4:c.391T>A
NR_164797.1:n.607T>A
NR_164798.1:n.610T>A

Protein change:

Y131N

Links:

dbSNP: rs2137081759

NCBI 1000 Genomes Browser:

rs2137081759

Molecular consequence:

NM_001376301.1:c.191-4924T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001128620.2:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376268.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376269.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376270.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376271.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376272.1:c.412T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376273.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376274.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376275.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376276.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376277.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376278.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376279.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376280.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376281.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376282.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376283.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376284.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376285.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376286.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376287.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376288.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376289.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376290.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376291.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376292.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376293.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376294.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376295.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376302.1:c.97T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376303.1:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376304.1:c.97T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001376305.1:c.97T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002576.5:c.391T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_164797.1:n.607T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_164798.1:n.610T>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001739320	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	no assertion criteria provided	Likely pathogenic (Jan 27, 2021)	germline	clinical testing
SCV002766913	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30290153, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001739320

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

no assertion criteria provided

Likely pathogenic
(Jan 27, 2021)

germline

clinical testing

SCV002766913

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 2, 2022)

germline

clinical testing

PubMed (2)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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

Details of each submission

From Clinical Genetics Laboratory, University Hospital Schleswig-Holstein, SCV001739320.1

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

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766913.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM#618158) (PMID: 30290153). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change to a cysteine has been reported in a de novo individual with neurodevelopmental disorder (PMID: 30290153). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported as likely pathogenic in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Dec 30, 2023

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