NM_007254.4(PNKP):c.1123G>T (p.Gly375Trp) AND Microcephaly, seizures, and developmental delay

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 5, 2022
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:: RCV001813762.10

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]

Observations:

Condition(s)

Name:: Microcephaly, seizures, and developmental delay
Synonyms:: Early infantile epileptic encephalopathy 10
Identifiers:: MONDO: MONDO:0013254; MedGen: C3150667; Orphanet: 1934; OMIM: 613402

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002061283	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 32010037, 32347949, 31061747, 31436889, 27890643, 27125728, 29652299, 25728773, 11704758, 18678442, 15136689, 24938145, 18845387, 21560189, 18005052, 18266750, 21307862, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002061283

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 5, 2022)

germline

clinical testing

PubMed (18)
[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	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Ferese R, Buttari F, Femiano C, Centonze D, Fornai F, Biagioni F, Chiaravalloti MA, Magnani M, Giardina E, Ruzzo A, Gambardella S.

Front Neurol. 2019;10:1331. doi: 10.3389/fneur.2019.01331.

PubMed [citation]

PMID:: 32010037
PMCID:: PMC6974581

Assessment of Interlaboratory Variation in the Interpretation of Genomic Test Results in Patients With Epilepsy.

SoRelle JA, Pascual JM, Gotway G, Park JY.

JAMA Netw Open. 2020 Apr 1;3(4):e203812. doi: 10.1001/jamanetworkopen.2020.3812.

PubMed [citation]

PMID:: 32347949
PMCID:: PMC7191323

See all PubMed Citations (18)

Details of each submission

From DASA, SCV002061283.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (18)

Description

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.

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

Last Updated: Sep 29, 2024

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