NM_007254.4(PNKP):c.1123G>T (p.Gly375Trp) AND Developmental and epileptic encephalopathy, 12

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 3, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000648410.16

Allele description [Variation Report for NM_007254.4(PNKP):c.1123G>T (p.Gly375Trp)]

NM_007254.4(PNKP):c.1123G>T (p.Gly375Trp)

Gene:

PNKP:polynucleotide kinase 3'-phosphatase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.33

Genomic location:

Preferred name:

NM_007254.4(PNKP):c.1123G>T (p.Gly375Trp)

HGVS:

NC_000019.10:g.49862188C>A
NG_027717.1:g.10378G>T
NG_050666.1:g.18345C>A
NM_007254.4:c.1123G>TMANE SELECT
NP_009185.2:p.Gly375Trp
NC_000019.9:g.50365445C>A
NM_007254.2:c.1123G>T
NM_007254.3:c.1123G>T
Q96T60:p.Gly375Trp

Protein change:

G375W; GLY375TRP

Links:

UniProtKB: Q96T60#VAR_073369; OMIM: 605610.0005; dbSNP: rs786203983

NCBI 1000 Genomes Browser:

rs786203983

Molecular consequence:

NM_007254.4:c.1123G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Developmental and epileptic encephalopathy, 12 (DEE12)
Synonyms:: Early infantile epileptic encephalopathy 12
Identifiers:: MONDO: MONDO:0013389; MedGen: C3150988; OMIM: 613722

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Menin is a ‘reader’ of histone H3 lysine 79 methylation (ChIP-Seq)
Menin is a ‘reader’ of histone H3 lysine 79 methylation (ChIP-Seq)

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000770230	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25728773, 31061747, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000770230

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 3, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4.

Bras J, Alonso I, Barbot C, Costa MM, Darwent L, Orme T, Sequeiros J, Hardy J, Coutinho P, Guerreiro R.

Am J Hum Genet. 2015 Mar 5;96(3):474-9. doi: 10.1016/j.ajhg.2015.01.005. Epub 2015 Feb 26.

PubMed [citation]

PMID:: 25728773
PMCID:: PMC4375449

Ataxia with Oculomotor Apraxia Type 4 with PNKP Common "Portuguese" and Novel Mutations in Two Belarusian Families.

Rudenskaya GE, Marakhonov AV, Shchagina OA, Lozier ER, Dadali EL, Akimova IA, Petrova NV, Konovalov FA.

J Pediatr Genet. 2019 Jun;8(2):58-62. doi: 10.1055/s-0039-1684008. Epub 2019 Mar 27.

PubMed [citation]

PMID:: 31061747
PMCID:: PMC6499616

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000770230.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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