The heterozygous one nucleotide deletion (c.387del, p.Glu129AspfsTer15) located in exon 4(of 16) of the PAK1 gene alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss-of-function is not an established mechanism of disease for PAK1. Gain-of-function has been shown as the likely mechanism of disease for the PAK1 gene [PMID:30290153; PMID: 31504246]. All pathogenic and likely pathogenic variants in PAK1gene reported to-date are missense [PMID:30290153; PMID: 31504246; PMID: 31392718]. The frameshift variant identified in this individual has 0.000007013 allele frequency in the gnomAD(v3) database (1 out of 142,600 heterozygous alleles, no homozygote) indicating it is an extremely rare allele in the populations represented in gnomAD(v3). This variant has not been reported in the literature in affected individuals to the best of our knowledge. Given the lack of compelling information regarding the pathogenicity of the frameshift variant identified in the PAK1 gene, it is reported as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_002576.5(PAK1):c.387del (p.Glu129fs)
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.
(1)
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.
Uncertain significance
1
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.387del (p.Glu129fs)
Variation ID: 1184425 Accession: VCV001184425.1
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 11q13.5 11: 77379293 (GRCh38) [ NCBI UCSC ] 11: 77090338 (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 28, 2021 Jul 28, 2021 Jul 17, 2020 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002576.5:c.387del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002567.3:p.Glu129fs frameshift NM_001128620.2:c.387del NP_001122092.1:p.Glu129fs frameshift NM_001376268.1:c.387del NP_001363197.1:p.Glu129fs frameshift NM_001376269.1:c.387del NP_001363198.1:p.Glu129fs frameshift NM_001376270.1:c.387del NP_001363199.1:p.Glu129fs frameshift NM_001376271.1:c.387del NP_001363200.1:p.Glu129fs frameshift NM_001376272.1:c.408del NP_001363201.1:p.Glu136fs frameshift NM_001376273.1:c.387del NP_001363202.1:p.Glu129fs frameshift NM_001376274.1:c.387del NP_001363203.1:p.Glu129fs frameshift NM_001376275.1:c.387del NP_001363204.1:p.Glu129fs frameshift NM_001376276.1:c.387del NP_001363205.1:p.Glu129fs frameshift NM_001376277.1:c.387del NP_001363206.1:p.Glu129fs frameshift NM_001376278.1:c.387del NP_001363207.1:p.Glu129fs frameshift NM_001376279.1:c.387del NP_001363208.1:p.Glu129fs frameshift NM_001376280.1:c.387del NP_001363209.1:p.Glu129fs frameshift NM_001376281.1:c.387del NP_001363210.1:p.Glu129fs frameshift NM_001376282.1:c.387del NP_001363211.1:p.Glu129fs frameshift NM_001376283.1:c.387del NP_001363212.1:p.Glu129fs frameshift NM_001376284.1:c.387del NP_001363213.1:p.Glu129fs frameshift NM_001376285.1:c.387del NP_001363214.1:p.Glu129fs frameshift NM_001376286.1:c.387del NP_001363215.1:p.Glu129fs frameshift NM_001376287.1:c.387del NP_001363216.1:p.Glu129fs frameshift NM_001376288.1:c.387del NP_001363217.1:p.Glu129fs frameshift NM_001376289.1:c.387del NP_001363218.1:p.Glu129fs frameshift NM_001376290.1:c.387del NP_001363219.1:p.Glu129fs frameshift NM_001376291.1:c.387del NP_001363220.1:p.Glu129fs frameshift NM_001376292.1:c.387del NP_001363221.1:p.Glu129fs frameshift NM_001376293.1:c.387del NP_001363222.1:p.Glu129fs frameshift NM_001376294.1:c.387del NP_001363223.1:p.Glu129fs frameshift NM_001376295.1:c.387del NP_001363224.1:p.Glu129fs frameshift NM_001376301.1:c.191-4928del intron variant NM_001376302.1:c.93del NP_001363231.1:p.Glu31fs frameshift NM_001376303.1:c.387del NP_001363232.1:p.Glu129fs frameshift NM_001376304.1:c.93del NP_001363233.1:p.Glu31fs frameshift NM_001376305.1:c.93del NP_001363234.1:p.Glu31fs frameshift NR_164797.1:n.603del non-coding transcript variant NR_164798.1:n.606del non-coding transcript variant NC_000011.10:g.77379293del NC_000011.9:g.77090338del NG_029900.2:g.99771del - Protein change
- E129fs, E136fs, E31fs
- Other names
- -
- Canonical SPDI
- NC_000011.10:77379292:C:
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- 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 |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Jul 17, 2020 | RCV001542445.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jul 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual developmental disorder with macrocephaly, seizures, and speech delay
Affected status: unknown
Allele origin:
germline
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001761152.1 First in ClinVar: Jul 28, 2021 Last updated: Jul 28, 2021 |
Comment:
The heterozygous one nucleotide deletion (c.387del, p.Glu129AspfsTer15) located in exon 4(of 16) of the PAK1 gene alters the wild-type translational reading frame and is predicted … (more)
The heterozygous one nucleotide deletion (c.387del, p.Glu129AspfsTer15) located in exon 4(of 16) of the PAK1 gene alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss-of-function is not an established mechanism of disease for PAK1. Gain-of-function has been shown as the likely mechanism of disease for the PAK1 gene [PMID:30290153; PMID: 31504246]. All pathogenic and likely pathogenic variants in PAK1gene reported to-date are missense [PMID:30290153; PMID: 31504246; PMID: 31392718]. The frameshift variant identified in this individual has 0.000007013 allele frequency in the gnomAD(v3) database (1 out of 142,600 heterozygous alleles, no homozygote) indicating it is an extremely rare allele in the populations represented in gnomAD(v3). This variant has not been reported in the literature in affected individuals to the best of our knowledge. Given the lack of compelling information regarding the pathogenicity of the frameshift variant identified in the PAK1 gene, it is reported as a Variant of Uncertain Significance. (less)
Clinical Features:
Seizure (present) , Intellectual disability (present) , Delayed speech and language development (present) , Premature birth (present) , Attention deficit hyperactivity disorder (present) , Asthma … (more)
Seizure (present) , Intellectual disability (present) , Delayed speech and language development (present) , Premature birth (present) , Attention deficit hyperactivity disorder (present) , Asthma (present) , Eczema (present) (less)
Secondary finding: no
|
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:
The heterozygous one nucleotide deletion (c.387del, p.Glu129AspfsTer15) located in exon 4(of 16) of the PAK1 gene alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss-of-function is not an established mechanism of disease for PAK1. Gain-of-function has been shown as the likely mechanism of disease for the PAK1 gene [PMID:30290153; PMID: 31504246]. All pathogenic and likely pathogenic variants in PAK1gene reported to-date are missense [PMID:30290153; PMID: 31504246; PMID: 31392718]. The frameshift variant identified in this individual has 0.000007013 allele frequency in the gnomAD(v3) database (1 out of 142,600 heterozygous alleles, no homozygote) indicating it is an extremely rare allele in the populations represented in gnomAD(v3). This variant has not been reported in the literature in affected individuals to the best of our knowledge. Given the lack of compelling information regarding the pathogenicity of the frameshift variant identified in the PAK1 gene, it is reported as a Variant of Uncertain Significance.
Citations for germline classification of this variant
Help| There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs1949516794 ...
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 Dec 25, 2023
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.