ClinVar Genomic variation as it relates to human health
NM_007254.4(PNKP):c.1123G>T (p.Gly375Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007254.4(PNKP):c.1123G>T (p.Gly375Trp)
Variation ID: 187766 Accession: VCV000187766.45
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.33 19: 49862188 (GRCh38) [ NCBI UCSC ] 19: 50365445 (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 Oct 7, 2016 Feb 20, 2024 Oct 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007254.4:c.1123G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009185.2:p.Gly375Trp missense NC_000019.10:g.49862188C>A NC_000019.9:g.50365445C>A NG_027717.1:g.10378G>T NG_050666.1:g.18345C>A Q96T60:p.Gly375Trp - Protein change
- G375W
- Other names
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- Canonical SPDI
- NC_000019.10:49862187:C:A
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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PNKP | - | - |
GRCh38 GRCh37 |
1127 | 1142 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
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Apr 27, 2023 | RCV000167523.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2017 | RCV000623823.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 3, 2023 | RCV000648410.15 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 16, 2023 | RCV001268912.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2022 | RCV001813762.10 |
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
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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
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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
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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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Pathogenic
(Jan 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly, seizures, and developmental delay
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002061283.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.1123G>T;p.(Gly375Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 187766; OMIM: 605610.0005; PMID: 32010037; … (more)
The c.1123G>T;p.(Gly375Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 187766; OMIM: 605610.0005; PMID: 32010037; 32347949; 31061747; 31436889; 27890643; 27125728; 29652299; 25728773) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (AAA_33 domain) - PM1. The variant is present at low allele frequencies population databases (rs786203983– gnomAD 0.0003943%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly375Trp) was detected in trans with a pathogenic variant (PMID: 31061747; 31436889; 27890643; 25728773) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID 25728773) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
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Pathogenic
(Feb 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742266.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Poor coordination (present) , Gait ataxia (present) , Spasticity (present) , Progressive muscle weakness (present) , Inability to walk (present) , Speech apraxia (present) , … (more)
Poor coordination (present) , Gait ataxia (present) , Spasticity (present) , Progressive muscle weakness (present) , Inability to walk (present) , Speech apraxia (present) , Autistic behavior (present) , Intellectual disability (present) , Nystagmus (present) , Dysmetria (present) , Dysdiadochokinesis (present) , Abnormality of the cerebellum (present) , Scanning speech (present) , Concave nail (present) (less)
Sex: male
Ethnicity/Population group: Hispanic
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Pathogenic
(Apr 27, 2023)
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criteria provided, single submitter
Method: research
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Ataxia - oculomotor apraxia type 4
Affected status: yes
Allele origin:
germline
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Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)
Accession: SCV003920796.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448161.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Seizure (present) , Oculomotor apraxia (present) , Cerebellar ataxia (present)
Sex: female
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Pathogenic
(Aug 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001805165.4
First in ClinVar: Aug 21, 2021 Last updated: Aug 24, 2023 |
Comment:
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; … (more)
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: 25728773, 29652299, 22508754, 33332469, 33956305, 35426160, 35187769, 31707899) (less)
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Pathogenic
(Oct 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 12
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000770230.6
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 375 of the PNKP protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 375 of the PNKP protein (p.Gly375Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia with oculomotor apraxia (PMID: 25728773, 31061747). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 187766). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PNKP protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 05, 2015)
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no assertion criteria provided
Method: literature only
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ATAXIA-OCULOMOTOR APRAXIA 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000218381.2
First in ClinVar: Mar 24, 2015 Last updated: Oct 07, 2016 |
Comment on evidence:
In 6 patients from 4 Portuguese families with ataxia-oculomotor apraxia-4 (AOA4; 616267), Bras et al. (2015) identified a homozygous c.1123G-T transversion in the PNKP gene, … (more)
In 6 patients from 4 Portuguese families with ataxia-oculomotor apraxia-4 (AOA4; 616267), Bras et al. (2015) identified a homozygous c.1123G-T transversion in the PNKP gene, resulting in a gly375-to-trp (G375W) substitution at a highly conserved residue in a potential ATP nucleotide-binding domain in the kinase region. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, was confirmed by Sanger sequencing and filtered against the dbSNP (build 137) database and an in-house database of over 2,000 samples. Affected individuals from 2 additional families were compound heterozygous for G375W and a frameshift mutation (605610.0002 and 605610.0006, respectively). All mutations segregated with the disorder in the families. Functional studies of the variants were not performed. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Assessment of Interlaboratory Variation in the Interpretation of Genomic Test Results in Patients With Epilepsy. | SoRelle JA | JAMA network open | 2020 | PMID: 32347949 |
A Novel Homozygous Variant in the Fork-Head-Associated Domain of Polynucleotide Kinase Phosphatase in a Patient Affected by Late-Onset Ataxia With Oculomotor Apraxia Type 4. | Campopiano R | Frontiers in neurology | 2020 | PMID: 32010037 |
From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with PNKP gene mutations. | Gatti M | American journal of medical genetics. Part A | 2019 | PMID: 31436889 |
Ataxia with Oculomotor Apraxia Type 4 with PNKP Common "Portuguese" and Novel Mutations in Two Belarusian Families. | Rudenskaya GE | Journal of pediatric genetics | 2019 | PMID: 31061747 |
[Ataxia with oculomotor apraxia type 4 detected by next-generation sequencing]. | Rudenskaya GE | Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova | 2018 | PMID: 29652299 |
Coordination of DNA single strand break repair. | Abbotts R | Free radical biology & medicine | 2017 | PMID: 27890643 |
Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease. | Dumitrache LC | Mechanisms of ageing and development | 2017 | PMID: 27125728 |
Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4. | Bras J | American journal of human genetics | 2015 | PMID: 25728773 |
Vanishing white matter disease presenting as opsoclonus myoclonus syndrome in childhood--a case report and review of the literature. | Klingelhoefer L | Pediatric neurology | 2014 | PMID: 24938145 |
Severity of vanishing white matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes. | Liu R | Human mutation | 2011 | PMID: 21560189 |
Functional analysis of recently identified mutations in eukaryotic translation initiation factor 2Bɛ (eIF2Bɛ) identified in Chinese patients with vanishing white matter disease. | Leng X | Journal of human genetics | 2011 | PMID: 21307862 |
Intra-familial phenotypic heterogeneity in adult onset vanishing white matter disease. | Damon-Perriere N | Clinical neurology and neurosurgery | 2008 | PMID: 18845387 |
The ovarioleukodystrophy. | Mathis S | Clinical neurology and neurosurgery | 2008 | PMID: 18678442 |
Leucoencephalopathy with vanishing white matter may cause progressive myoclonus epilepsy. | Jansen AC | Epilepsia | 2008 | PMID: 18266750 |
Acute neurological deterioration in ovarioleukodystrophy related to EIF2B mutations: pregnancy with oocyte donation is a potentially precipitating factor. | Peter L | European journal of neurology | 2008 | PMID: 18005052 |
Arg113His mutation in eIF2Bepsilon as cause of leukoencephalopathy in adults. | van der Knaap MS | Neurology | 2004 | PMID: 15136689 |
Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. | Leegwater PA | Nature genetics | 2001 | PMID: 11704758 |
Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3'-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage. | Jilani A | The Journal of biological chemistry | 1999 | PMID: 10446192 |
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Text-mined citations for rs786203983 ...
HelpRecord last updated Jun 23, 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.