VCV001174490.3 - ClinVar

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

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.

(2)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 1174490 Accession: VCV001174490.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.5 11: 77379289 (GRCh38) [ NCBI UCSC ] 11: 77090334 (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	Jul 7, 2021	Dec 24, 2022	Sep 2, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_002576.5:c.391T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002567.3:p.Tyr131Asn	missense
NM_001128620.2:c.391T>A	NP_001122092.1:p.Tyr131Asn	missense
NM_001376268.1:c.391T>A	NP_001363197.1:p.Tyr131Asn	missense
NM_001376269.1:c.391T>A	NP_001363198.1:p.Tyr131Asn	missense
NM_001376270.1:c.391T>A	NP_001363199.1:p.Tyr131Asn	missense
NM_001376271.1:c.391T>A	NP_001363200.1:p.Tyr131Asn	missense
NM_001376272.1:c.412T>A	NP_001363201.1:p.Tyr138Asn	missense
NM_001376273.1:c.391T>A	NP_001363202.1:p.Tyr131Asn	missense
NM_001376274.1:c.391T>A	NP_001363203.1:p.Tyr131Asn	missense
NM_001376275.1:c.391T>A	NP_001363204.1:p.Tyr131Asn	missense
NM_001376276.1:c.391T>A	NP_001363205.1:p.Tyr131Asn	missense
NM_001376277.1:c.391T>A	NP_001363206.1:p.Tyr131Asn	missense
NM_001376278.1:c.391T>A	NP_001363207.1:p.Tyr131Asn	missense
NM_001376279.1:c.391T>A	NP_001363208.1:p.Tyr131Asn	missense
NM_001376280.1:c.391T>A	NP_001363209.1:p.Tyr131Asn	missense
NM_001376281.1:c.391T>A	NP_001363210.1:p.Tyr131Asn	missense
NM_001376282.1:c.391T>A	NP_001363211.1:p.Tyr131Asn	missense
NM_001376283.1:c.391T>A	NP_001363212.1:p.Tyr131Asn	missense
NM_001376284.1:c.391T>A	NP_001363213.1:p.Tyr131Asn	missense
NM_001376285.1:c.391T>A	NP_001363214.1:p.Tyr131Asn	missense
NM_001376286.1:c.391T>A	NP_001363215.1:p.Tyr131Asn	missense
NM_001376287.1:c.391T>A	NP_001363216.1:p.Tyr131Asn	missense
NM_001376288.1:c.391T>A	NP_001363217.1:p.Tyr131Asn	missense
NM_001376289.1:c.391T>A	NP_001363218.1:p.Tyr131Asn	missense
NM_001376290.1:c.391T>A	NP_001363219.1:p.Tyr131Asn	missense
NM_001376291.1:c.391T>A	NP_001363220.1:p.Tyr131Asn	missense
NM_001376292.1:c.391T>A	NP_001363221.1:p.Tyr131Asn	missense
NM_001376293.1:c.391T>A	NP_001363222.1:p.Tyr131Asn	missense
NM_001376294.1:c.391T>A	NP_001363223.1:p.Tyr131Asn	missense
NM_001376295.1:c.391T>A	NP_001363224.1:p.Tyr131Asn	missense
NM_001376301.1:c.191-4924T>A		intron variant
NM_001376302.1:c.97T>A	NP_001363231.1:p.Tyr33Asn	missense
NM_001376303.1:c.391T>A	NP_001363232.1:p.Tyr131Asn	missense
NM_001376304.1:c.97T>A	NP_001363233.1:p.Tyr33Asn	missense
NM_001376305.1:c.97T>A	NP_001363234.1:p.Tyr33Asn	missense
NM_002576.4:c.391T>A
NR_164797.1:n.607T>A		non-coding transcript variant
NR_164798.1:n.610T>A		non-coding transcript variant
NC_000011.10:g.77379289A>T
NC_000011.9:g.77090334A>T
NG_029900.2:g.99775T>A

... more HGVS ... less HGVS

Protein change

Y131N, Y138N, Y33N

Other names

Canonical SPDI

NC_000011.10:77379288:A: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: rs2137081759 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.
PAK1		-	-	GRCh38 GRCh37	93	102

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.
Intellectual developmental disorder with macrocephaly, seizures, and speech delay	Pathogenic (2)	criteria provided, single submitter	Sep 2, 2022	RCV001528115.3

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.
Pathogenic (Sep 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual developmental disorder with macrocephaly, seizures, and speech delay (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002766913.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 30290153 Comment: 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 … (more) 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 (less)
Likely pathogenic (Jan 27, 2021)	no assertion criteria provided Method: clinical testing	Intellectual developmental disorder with macrocephaly, seizures, and speech delay Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV001739320.1 First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021

Comment:

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

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
Activating Mutations in PAK1, Encoding p21-Activated Kinase 1, Cause a Neurodevelopmental Disorder.	Harms FL	American journal of human genetics	2018	PMID: 30290153

Text-mined citations for rs2137081759 ...

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 Dec 30, 2023

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2137081759 ...