NM_001386393.1(PANK2):c.370A>G (p.Thr124Ala) AND Pigmentary pallidal degeneration

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Dec 21, 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:: RCV001851655.5

Allele description [Variation Report for NM_001386393.1(PANK2):c.370A>G (p.Thr124Ala)]

NM_001386393.1(PANK2):c.370A>G (p.Thr124Ala)

Gene:

PANK2:pantothenate kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20p13

Genomic location:

Preferred name:

NM_001386393.1(PANK2):c.370A>G (p.Thr124Ala)

Other names:

T124A

HGVS:

NC_000020.11:g.3907997A>G
NG_008131.3:g.24159A>G
NM_001324191.2:c.-174A>G
NM_001324192.1:c.700A>G
NM_001324193.2:c.-466A>G
NM_001386393.1:c.370A>GMANE SELECT
NM_024960.6:c.-174A>G
NM_153638.3:c.700A>G
NM_153638.4:c.700A>G
NM_153640.4:c.-174A>G
NP_001311121.1:p.Thr234Ala
NP_001373322.1:p.Thr124Ala
NP_705902.2:p.Thr234Ala
LRG_1016t1:c.700A>G
LRG_1016t2:c.370A>G
LRG_1016:g.24159A>G
LRG_1016p1:p.Thr234Ala
LRG_1016p2:p.Thr124Ala
NC_000020.10:g.3888644A>G
NR_136715.2:n.414A>G
Q9BZ23:p.Thr234Ala

Protein change:

T234A; THR124ALA

Links:

UniProtKB: Q9BZ23#VAR_015155; OMIM: 606157.0008; dbSNP: rs137852965

NCBI 1000 Genomes Browser:

rs137852965

Molecular consequence:

NM_001324191.2:c.-174A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001324193.2:c.-466A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_024960.6:c.-174A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_153640.4:c.-174A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001324192.1:c.700A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001386393.1:c.370A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_153638.4:c.700A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_136715.2:n.414A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Pigmentary pallidal degeneration (NBIA1)
Synonyms:: PKAN NEUROAXONAL DYSTROPHY, JUVENILE-ONSET; Pantothenate kinase-associated neurodegeneration; Neuroaxonal dystrophy, late infantile; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009319; MedGen: C0018523; Orphanet: 157850; OMIM: 234200

Recent activity

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Homo sapiens recombination signal binding protein for immunoglobulin kappa J reg...
Homo sapiens recombination signal binding protein for immunoglobulin kappa J region (RBPJ), transcript variant 1, mRNA
gi|350606365|ref|NM_005349.3|

Nucleotide
hypothetical protein Naga_101508g3 [Nannochloropsis gaditana]
hypothetical protein Naga_101508g3 [Nannochloropsis gaditana]
gi|585099533|gb|EWM20145.1||gnl|WGS |Naga_101508g3.2451

Protein
LOC120019553 [Salvelinus namaycush]
LOC120019553 [Salvelinus namaycush]
Gene ID:120019553

Gene
Profile neighbors for GEO Profiles (Select 103774822) (200)
GEO Profiles
Chromosome neighbors for GEO Profiles (Select 103774822) (20)
GEO Profiles

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024990	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2001)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002162930	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11479594, 16023068, 26547561, 15659606, 23166001, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000024990

OMIM

no assertion criteria provided

Pathogenic
(Aug 1, 2001)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002162930

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 21, 2023)

germline

clinical testing

PubMed (6)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome.

Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ.

Nat Genet. 2001 Aug;28(4):345-9.

PubMed [citation]

PMID:: 11479594

Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome).

Egan RA, Weleber RG, Hogarth P, Gregory A, Coryell J, Westaway SK, Gitschier J, Das S, Hayflick SJ.

Am J Ophthalmol. 2005 Aug;140(2):267-74.

PubMed [citation]

PMID:: 16023068
PMCID:: PMC2169522

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000024990.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In an individual with atypical pantothenate kinase-associated neurodegeneration (NBIA1; 234200), Zhou et al. (2001) identified an A-to-G transition at nucleotide 400 of the PANK2 gene, resulting in a threonine-to-alanine substitution at codon 124 (T124A).

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002162930.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 234 of the PANK2 protein (p.Thr234Ala). This variant is present in population databases (rs137852965, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of pantothenate kinase-associated neurodegeneration (PMID: 11479594, 16023068, 26547561). This variant is also known as c.400A>G (p.T124A) or c.370A>G. ClinVar contains an entry for this variant (Variation ID: 4554). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PANK2 protein function. Experimental studies have shown that this missense change does not substantially affect PANK2 function (PMID: 15659606). This variant disrupts the p.Thr234 amino acid residue in PANK2. Other variant(s) that disrupt this residue have been observed in individuals with PANK2-related conditions (PMID: 23166001), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Oct 20, 2024

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