This variant is interpreted as a Likely pathogenic for Intellectual developmental disorder with macrocephaly, seizures, and speech delay, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PP3, PM6, PS3.
ClinVar Genomic variation as it relates to human health
NM_002576.5(PAK1):c.392A>G (p.Tyr131Cys)
Germline
Classification
Help
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)
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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.
Likely pathogenic
2
criteria provided, single submitter
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002576.5(PAK1):c.392A>G (p.Tyr131Cys)
Variation ID: 587370 Accession: VCV000587370.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.5 11: 77379288 (GRCh38) [ NCBI UCSC ] 11: 77090333 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Nov 5, 2018 Nov 2, 2019 Feb 20, 2019 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002576.5:c.392A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002567.3:p.Tyr131Cys missense NM_001128620.2:c.392A>G NP_001122092.1:p.Tyr131Cys missense NM_001376268.1:c.392A>G NP_001363197.1:p.Tyr131Cys missense NM_001376269.1:c.392A>G NP_001363198.1:p.Tyr131Cys missense NM_001376270.1:c.392A>G NP_001363199.1:p.Tyr131Cys missense NM_001376271.1:c.392A>G NP_001363200.1:p.Tyr131Cys missense NM_001376272.1:c.413A>G NP_001363201.1:p.Tyr138Cys missense NM_001376273.1:c.392A>G NP_001363202.1:p.Tyr131Cys missense NM_001376274.1:c.392A>G NP_001363203.1:p.Tyr131Cys missense NM_001376275.1:c.392A>G NP_001363204.1:p.Tyr131Cys missense NM_001376276.1:c.392A>G NP_001363205.1:p.Tyr131Cys missense NM_001376277.1:c.392A>G NP_001363206.1:p.Tyr131Cys missense NM_001376278.1:c.392A>G NP_001363207.1:p.Tyr131Cys missense NM_001376279.1:c.392A>G NP_001363208.1:p.Tyr131Cys missense NM_001376280.1:c.392A>G NP_001363209.1:p.Tyr131Cys missense NM_001376281.1:c.392A>G NP_001363210.1:p.Tyr131Cys missense NM_001376282.1:c.392A>G NP_001363211.1:p.Tyr131Cys missense NM_001376283.1:c.392A>G NP_001363212.1:p.Tyr131Cys missense NM_001376284.1:c.392A>G NP_001363213.1:p.Tyr131Cys missense NM_001376285.1:c.392A>G NP_001363214.1:p.Tyr131Cys missense NM_001376286.1:c.392A>G NP_001363215.1:p.Tyr131Cys missense NM_001376287.1:c.392A>G NP_001363216.1:p.Tyr131Cys missense NM_001376288.1:c.392A>G NP_001363217.1:p.Tyr131Cys missense NM_001376289.1:c.392A>G NP_001363218.1:p.Tyr131Cys missense NM_001376290.1:c.392A>G NP_001363219.1:p.Tyr131Cys missense NM_001376291.1:c.392A>G NP_001363220.1:p.Tyr131Cys missense NM_001376292.1:c.392A>G NP_001363221.1:p.Tyr131Cys missense NM_001376293.1:c.392A>G NP_001363222.1:p.Tyr131Cys missense NM_001376294.1:c.392A>G NP_001363223.1:p.Tyr131Cys missense NM_001376295.1:c.392A>G NP_001363224.1:p.Tyr131Cys missense NM_001376301.1:c.191-4923A>G intron variant NM_001376302.1:c.98A>G NP_001363231.1:p.Tyr33Cys missense NM_001376303.1:c.392A>G NP_001363232.1:p.Tyr131Cys missense NM_001376304.1:c.98A>G NP_001363233.1:p.Tyr33Cys missense NM_001376305.1:c.98A>G NP_001363234.1:p.Tyr33Cys missense NR_164797.1:n.608A>G non-coding transcript variant NR_164798.1:n.611A>G non-coding transcript variant NC_000011.10:g.77379288T>C NC_000011.9:g.77090333T>C NG_029900.2:g.99776A>G - Protein change
- Y131C, Y138C, Y33C
- Other names
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- Canonical SPDI
- NC_000011.10:77379287:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| 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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, single submitter
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Feb 20, 2019 | RCV000714509.3 |
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. |
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Likely pathogenic
(Feb 20, 2019)
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criteria provided, single submitter
Method: curation
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Intellectual developmental disorder with macrocephaly, seizures, and speech delay
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000996452.1
First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019 |
Comment:
This variant is interpreted as a Likely pathogenic for Intellectual developmental disorder with macrocephaly, seizures, and speech delay, autosomal dominant. The following ACMG Tag(s) were … (more)
This variant is interpreted as a Likely pathogenic for Intellectual developmental disorder with macrocephaly, seizures, and speech delay, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PP3, PM6, PS3. (less)
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Pathogenic
(Oct 31, 2018)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER WITH MACROCEPHALY, SEIZURES, AND SPEECH DELAY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000845199.1
First in ClinVar: Nov 05, 2018 Last updated: Nov 05, 2018 |
Comment on evidence:
In a 7-year-old boy (patient 1), born of consanguineous Arabian parents, with intellectual developmental disorder with macrocephaly, seizures, and speech delay (IDDMSSD; 618158), Harms et … (more)
In a 7-year-old boy (patient 1), born of consanguineous Arabian parents, with intellectual developmental disorder with macrocephaly, seizures, and speech delay (IDDMSSD; 618158), Harms et al. (2018) identified a de novo heterozygous c.392A-G transition (c.392A-G, NM_001128620.1) in the PAK1 gene, resulting in a tyr131-to-cys (Y131C) substitution at a highly conserved residue in the autoinhibitory (AID) domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, ExAC, or gnomAD databases. The patient also carried variants in another gene that were not thought to contribute to the phenotype. Patient fibroblasts showed increased phosphorylation of downstream PAK1 targets, including JNK1 (MAPK8; 601158), AKT1 (164730), and JUN (165160), as well as a trend towards increased PAK1 kinase activity compared to controls, suggesting that the mutation resulted in a gain of function. Harms et al. (2018) hypothesized that the mutation in the AID domain could disrupt dimerization and negatively affect trans-inhibition. (less)
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Comment:
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:
This variant is interpreted as a Likely pathogenic for Intellectual developmental disorder with macrocephaly, seizures, and speech delay, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PP3, PM6, PS3.
Citations for germline classification of this variant
Help| 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 rs1565638316 ...
HelpThese 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 Apr 25, 2022
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.