The PAK1 c.362C>T (p.Pro121Leu) missense variant has not been reported in the literature in association with PAK1-related neurodevelopmental disorders. However, a different variant at the same amino acid position, c.361C>T (p.Pro121Ser), has been described in a de novo, heterozygous state in a 20 year-old male with intellectual disability, macrocephaly, tremor (onset at age 10 years), mild ataxia and abnormalities on brain MRI (Horn et al. 2019). Control data are not available for the p.Pro121Leu variant, which is not reported in the Genome Aggregation Database in a region of good sequence coverage, so is presumed to be rare. The p.Pro121Leu variant is located in the functionally important autoregulatory domain of the protein (Horn et al. 2019). Based on the occurrence of the variant de novo, the identification of a pathogenic variant at the same amino acid position, absence of the variant from population databases and application of ACMG criteria, the p.Pro121Leu variant is classified as pathogenic for PAK1-related neurodevelopmental disorders.
ClinVar Genomic variation as it relates to human health
NM_002576.5(PAK1):c.362C>T (p.Pro121Leu)
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.
(3)
Help
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
3
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002576.5(PAK1):c.362C>T (p.Pro121Leu)
Variation ID: 973272 Accession: VCV000973272.6
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.5 11: 77379318 (GRCh38) [ NCBI UCSC ] 11: 77090363 (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 25, 2020 Oct 8, 2024 Jun 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002576.5:c.362C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002567.3:p.Pro121Leu missense NM_001128620.2:c.362C>T NP_001122092.1:p.Pro121Leu missense NM_001376268.1:c.362C>T NP_001363197.1:p.Pro121Leu missense NM_001376269.1:c.362C>T NP_001363198.1:p.Pro121Leu missense NM_001376270.1:c.362C>T NP_001363199.1:p.Pro121Leu missense NM_001376271.1:c.362C>T NP_001363200.1:p.Pro121Leu missense NM_001376272.1:c.383C>T NP_001363201.1:p.Pro128Leu missense NM_001376273.1:c.362C>T NP_001363202.1:p.Pro121Leu missense NM_001376274.1:c.362C>T NP_001363203.1:p.Pro121Leu missense NM_001376275.1:c.362C>T NP_001363204.1:p.Pro121Leu missense NM_001376276.1:c.362C>T NP_001363205.1:p.Pro121Leu missense NM_001376277.1:c.362C>T NP_001363206.1:p.Pro121Leu missense NM_001376278.1:c.362C>T NP_001363207.1:p.Pro121Leu missense NM_001376279.1:c.362C>T NP_001363208.1:p.Pro121Leu missense NM_001376280.1:c.362C>T NP_001363209.1:p.Pro121Leu missense NM_001376281.1:c.362C>T NP_001363210.1:p.Pro121Leu missense NM_001376282.1:c.362C>T NP_001363211.1:p.Pro121Leu missense NM_001376283.1:c.362C>T NP_001363212.1:p.Pro121Leu missense NM_001376284.1:c.362C>T NP_001363213.1:p.Pro121Leu missense NM_001376285.1:c.362C>T NP_001363214.1:p.Pro121Leu missense NM_001376286.1:c.362C>T NP_001363215.1:p.Pro121Leu missense NM_001376287.1:c.362C>T NP_001363216.1:p.Pro121Leu missense NM_001376288.1:c.362C>T NP_001363217.1:p.Pro121Leu missense NM_001376289.1:c.362C>T NP_001363218.1:p.Pro121Leu missense NM_001376290.1:c.362C>T NP_001363219.1:p.Pro121Leu missense NM_001376291.1:c.362C>T NP_001363220.1:p.Pro121Leu missense NM_001376292.1:c.362C>T NP_001363221.1:p.Pro121Leu missense NM_001376293.1:c.362C>T NP_001363222.1:p.Pro121Leu missense NM_001376294.1:c.362C>T NP_001363223.1:p.Pro121Leu missense NM_001376295.1:c.362C>T NP_001363224.1:p.Pro121Leu missense NM_001376301.1:c.191-4953C>T intron variant NM_001376302.1:c.68C>T NP_001363231.1:p.Pro23Leu missense NM_001376303.1:c.362C>T NP_001363232.1:p.Pro121Leu missense NM_001376304.1:c.68C>T NP_001363233.1:p.Pro23Leu missense NM_001376305.1:c.68C>T NP_001363234.1:p.Pro23Leu missense NR_164797.1:n.578C>T non-coding transcript variant NR_164798.1:n.581C>T non-coding transcript variant NC_000011.10:g.77379318G>A NC_000011.9:g.77090363G>A NG_029900.2:g.99746C>T - Protein change
- P128L, P121L, P23L
- Other names
- -
- Canonical SPDI
- NC_000011.10:77379317:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| PAK1 | - | - |
GRCh38 GRCh37 |
95 | 104 | |
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. |
|---|---|---|---|---|
|
PAK1-related neurodevelopmental disorders
|
Pathogenic (1) |
criteria provided, single submitter
|
Dec 4, 2019 | RCV001249699.4 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 11, 2024 | RCV001806087.3 | |
|
PAK1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Mar 21, 2023 | RCV003399021.4 |
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
(Dec 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
PAK1-related neurodevelopmental disorders
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV001423721.2
First in ClinVar: Jul 25, 2020 Last updated: Mar 04, 2023 |
Comment:
The PAK1 c.362C>T (p.Pro121Leu) missense variant has not been reported in the literature in association with PAK1-related neurodevelopmental disorders. However, a different variant at the … (more)
The PAK1 c.362C>T (p.Pro121Leu) missense variant has not been reported in the literature in association with PAK1-related neurodevelopmental disorders. However, a different variant at the same amino acid position, c.361C>T (p.Pro121Ser), has been described in a de novo, heterozygous state in a 20 year-old male with intellectual disability, macrocephaly, tremor (onset at age 10 years), mild ataxia and abnormalities on brain MRI (Horn et al. 2019). Control data are not available for the p.Pro121Leu variant, which is not reported in the Genome Aggregation Database in a region of good sequence coverage, so is presumed to be rare. The p.Pro121Leu variant is located in the functionally important autoregulatory domain of the protein (Horn et al. 2019). Based on the occurrence of the variant de novo, the identification of a pathogenic variant at the same amino acid position, absence of the variant from population databases and application of ACMG criteria, the p.Pro121Leu variant is classified as pathogenic for PAK1-related neurodevelopmental disorders. (less)
|
|
|
Pathogenic
(Mar 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PAK1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004110341.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PAK1 c.362C>T variant is predicted to result in the amino acid substitution p.Pro121Leu. This variant has been previously reported as a de novo finding … (more)
The PAK1 c.362C>T variant is predicted to result in the amino acid substitution p.Pro121Leu. This variant has been previously reported as a de novo finding in one patient with severe regressive autism, intellectual disability, macrocephaly and epilepsy. Functional analyses using the patient's cells showed that the presence of PAK1 p.Pro121Leu substitution results in misregulated PAK1-dependent pathways, altered cytoskeletal organization, and early attenuation of cellular proliferation (Kernohan et al. 2019. PubMed ID: 31392718). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. An alternate nucleotide change affecting the same amino acid (p.Pro121Ser) has been reported as de novo in a patient with hypotonia, ADHD, developmental delay, tremors, ataxia, and macrocephaly (Patient 3, Horn et al. 2019. PubMed:1504246). In summary, this variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Jun 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002050641.3
First in ClinVar: Jan 08, 2022 Last updated: Oct 08, 2024 |
Comment:
Published functional studies on patient fibroblasts suggest this variant results in impairment of PAK1 function, however additional studies are needed to validate the functional effect … (more)
Published functional studies on patient fibroblasts suggest this variant results in impairment of PAK1 function, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 31392718); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31392718, 27535533) (less)
|
Comment:
Comment:
The PAK1 c.362C>T variant is predicted to result in the amino acid substitution p.Pro121Leu. This variant has been previously reported as a de novo finding in one patient with severe regressive autism, intellectual disability, macrocephaly and epilepsy. Functional analyses using the patient's cells showed that the presence of PAK1 p.Pro121Leu substitution results in misregulated PAK1-dependent pathways, altered cytoskeletal organization, and early attenuation of cellular proliferation (Kernohan et al. 2019. PubMed ID: 31392718). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. An alternate nucleotide change affecting the same amino acid (p.Pro121Ser) has been reported as de novo in a patient with hypotonia, ADHD, developmental delay, tremors, ataxia, and macrocephaly (Patient 3, Horn et al. 2019. PubMed:1504246). In summary, this variant is interpreted as pathogenic.
Comment:
Published functional studies on patient fibroblasts suggest this variant results in impairment of PAK1 function, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 31392718); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31392718, 27535533)
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:
The PAK1 c.362C>T (p.Pro121Leu) missense variant has not been reported in the literature in association with PAK1-related neurodevelopmental disorders. However, a different variant at the same amino acid position, c.361C>T (p.Pro121Ser), has been described in a de novo, heterozygous state in a 20 year-old male with intellectual disability, macrocephaly, tremor (onset at age 10 years), mild ataxia and abnormalities on brain MRI (Horn et al. 2019). Control data are not available for the p.Pro121Leu variant, which is not reported in the Genome Aggregation Database in a region of good sequence coverage, so is presumed to be rare. The p.Pro121Leu variant is located in the functionally important autoregulatory domain of the protein (Horn et al. 2019). Based on the occurrence of the variant de novo, the identification of a pathogenic variant at the same amino acid position, absence of the variant from population databases and application of ACMG criteria, the p.Pro121Leu variant is classified as pathogenic for PAK1-related neurodevelopmental disorders.
Comment:
The PAK1 c.362C>T variant is predicted to result in the amino acid substitution p.Pro121Leu. This variant has been previously reported as a de novo finding in one patient with severe regressive autism, intellectual disability, macrocephaly and epilepsy. Functional analyses using the patient's cells showed that the presence of PAK1 p.Pro121Leu substitution results in misregulated PAK1-dependent pathways, altered cytoskeletal organization, and early attenuation of cellular proliferation (Kernohan et al. 2019. PubMed ID: 31392718). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. An alternate nucleotide change affecting the same amino acid (p.Pro121Ser) has been reported as de novo in a patient with hypotonia, ADHD, developmental delay, tremors, ataxia, and macrocephaly (Patient 3, Horn et al. 2019. PubMed:1504246). In summary, this variant is interpreted as pathogenic.
Comment:
Published functional studies on patient fibroblasts suggest this variant results in impairment of PAK1 function, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 31392718); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31392718, 27535533)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures. | Horn S | Brain : a journal of neurology | 2019 | PMID: 31504246 |
Text-mined citations for rs1949519149 ...
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 Oct 08, 2024
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.