VCV000854429.16 - ClinVar

NM_007254.4(PNKP):c.1549C>T (p.Gln517Ter)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic (1); Uncertain significance (3)

4 out of 6 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_007254.4(PNKP):c.1549C>T (p.Gln517Ter)

Variation ID: 854429 Accession: VCV000854429.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.33 19: 49861265 (GRCh38) [ NCBI UCSC ] 19: 50364522 (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	Apr 15, 2020	Mar 7, 2026	Dec 21, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_007254.4:c.1549C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009185.2:p.Gln517Ter	nonsense
NC_000019.10:g.49861265G>A
NC_000019.9:g.50364522G>A
NG_027717.1:g.11301C>T
NG_050666.1:g.17422G>A

... more HGVS ... less HGVS

Protein change

Q517*

Other names

Canonical SPDI

NC_000019.10:49861264:G:A

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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00007

The Genome Aggregation Database (gnomAD) 0.00017

The Genome Aggregation Database (gnomAD) 0.00019

Trans-Omics for Precision Medicine (TOPMed) 0.00022

Links

ClinGen: CA9586310 OMIM: 605610.0009 dbSNP: rs774995635 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.
PNKP		-	-	GRCh38 GRCh37	1276	1292

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.
Developmental and epileptic encephalopathy, 12	Pathogenic (1)	criteria provided, single submitter	Dec 21, 2025	RCV001059483.10
Charcot-Marie-Tooth disease type 2B2	Pathogenic (1)	no assertion criteria provided	May 7, 2020	RCV001093541.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Apr 25, 2023	RCV001552324.3
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Mar 31, 2020	RCV002402427.2
Abnormal cerebral morphology	Pathogenic (1)	no assertion criteria provided	-	RCV002275195.1
Charcot-Marie-Tooth disease type 2B2 Microcephaly, seizures, and developmental delay	Uncertain significance (1)	criteria provided, single submitter	Feb 13, 2024	RCV005409767.1

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.	Expand all rows Collapse all rows 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 (Apr 25, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001772992.2 First in ClinVar: Aug 07, 2021 Last updated: May 06, 2023	Comment: show Observed in apparent homozygous state in members of a consanguineous family and observed multiple times with another PNKP variantin unrelated patients in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes; all are described as having Charcot Marie Tooth disease type 2 (Leal et al., 2018); Nonsense variant predicted to result in protein truncation as the last 5 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 19290556, 30956058, 31436889, 22508754, 30039206) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Mar 31, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Inborn genetic diseases	Ambry Genetics Accession: SCV002709411.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 15749016‚ 30039206 Comment: show The p.Q517* variant (also known as c.1549C>T), located in coding exon 16 of the PNKP gene, results from a C to T substitution at nucleotide position 1549. This changes the amino acid from a glutamine to a stop codon within coding exon 16. In a large Costa Rican family, this variant was homozygous in individuals with Charcot-Marie-Tooth (CMT) disease with axonal neuropathy and autosomal recessive pattern of inheritance; all the affected individuals were also homozygous for the p.A335V MED25 variant (Leal A et al. Neurogenetics, 2018 12;19:215-225). In five other Costa Rican families with CMT, this variant was compound heterozygous with another PNKP nonsense variant in affected individuals; these individuals were also heterozygous for the p.A335V MED25 variant, suggesting a common ancestral haploytpe. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of PNKP, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 5 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. Based on available evidence to date, the clinical significance of this alteration remains unclear. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Dec 21, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Developmental and epileptic encephalopathy, 12	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001224107.7 First in ClinVar: Apr 15, 2020 Last updated: Mar 07, 2026	Publications: PubMed (1) PubMed: 30039206 Comment: show This sequence change creates a premature translational stop signal (p.Gln517*) in the PNKP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the PNKP protein. This variant is present in population databases (rs774995635, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individuals with clinical features of Charcot-Marie-Tooth disease (PMID: 30039206). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 854429). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Feb 13, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Microcephaly, seizures, and developmental delay Charcot-Marie-Tooth disease type 2B2 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. (Autosomal recessive inheritance)	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV006075136.1 First in ClinVar: May 15, 2025 Last updated: May 15, 2025	Comment: show PM2 BS2 PP5_supporting PVS1_moderate (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (May 07, 2020) N Not contributing to aggregate classification	no assertion criteria provided	CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B2	OMIM Accession: SCV001250590.1 First in ClinVar: May 12, 2020 Last updated: May 12, 2020	Publications: PubMed (2) PubMed: 11112660‚ 30039206 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In affected members of a large multigenerational consanguineous Costa Rican family with Charcot-Marie-Tooth disease type 2B2 (CMT2B2; 605589), originally reported by Leal et al. (2001), … (more) In affected members of a large multigenerational consanguineous Costa Rican family with Charcot-Marie-Tooth disease type 2B2 (CMT2B2; 605589), originally reported by Leal et al. (2001), Leal et al. (2018) identified a homozygous c.1549C-T transition in the last exon (exon 17) of the PNKP gene, resulting in a gln517-to-ter (Q517X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant has a low frequency in the gnomAD database (18 of 245,644 alleles). Previously, the disorder in this family was erroneously attributed to a homozygous variant in the MED25 gene (A335V; 610197.0001), which maps to the same region as PNKP. The MED25 and PNKP variants both fully segregated with the disorder in the family and were shown to be present on the same haplotype, suggesting an ancestral founder haplotype. Analysis of the PNKP coding sequencing in 5 additional Costa Rican probands with a similar phenotype showed that all were compound heterozygous for the Q517X mutation and a Thr408del (605610.0007) mutation. These patients also carried the ancestral haplotype with the MED25 variant. Molecular modeling predicted a damaging effect for the Q517X mutation, although functional studies and studies of patient cells were not performed. Leal et al. (2018) concluded that the mutant protein would lack an important functional C-terminal domain, causing increased DNA damage with subsequent cell death. (less)

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Abnormal cerebral morphology	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV002562837.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022	Observation: 1 Collection method: clinical testing Allele origin: paternal Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: paternal Affected status: yes Zygosity: 1 Compound Heterozygote

Comment:

Observed in apparent homozygous state in members of a consanguineous family and observed multiple times with another PNKP variantin unrelated patients in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes; all are described as having Charcot Marie Tooth disease type 2 (Leal et al., 2018); Nonsense variant predicted to result in protein truncation as the last 5 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 19290556, 30956058, 31436889, 22508754, 30039206)

Comment:

The p.Q517* variant (also known as c.1549C>T), located in coding exon 16 of the PNKP gene, results from a C to T substitution at nucleotide position 1549. This changes the amino acid from a glutamine to a stop codon within coding exon 16. In a large Costa Rican family, this variant was homozygous in individuals with Charcot-Marie-Tooth (CMT) disease with axonal neuropathy and autosomal recessive pattern of inheritance; all the affected individuals were also homozygous for the p.A335V MED25 variant (Leal A et al. Neurogenetics, 2018 12;19:215-225). In five other Costa Rican families with CMT, this variant was compound heterozygous with another PNKP nonsense variant in affected individuals; these individuals were also heterozygous for the p.A335V MED25 variant, suggesting a common ancestral haploytpe. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of PNKP, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 5 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. Based on available evidence to date, the clinical significance of this alteration remains unclear.

Comment:

This sequence change creates a premature translational stop signal (p.Gln517*) in the PNKP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the PNKP protein. This variant is present in population databases (rs774995635, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individuals with clinical features of Charcot-Marie-Tooth disease (PMID: 30039206). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 854429). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25.	Leal A	Neurogenetics	2018	PMID: 30039206
The molecular architecture of the mammalian DNA repair enzyme, polynucleotide kinase.	Bernstein NK	Molecular cell	2005	PMID: 15749016
A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3.	Leal A	American journal of human genetics	2001	PMID: 11112660

Text-mined citations for rs774995635 ...

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 Apr 13, 2026