NM_001386393.1(PANK2):c.988C>T (p.Arg330Cys) AND Pigmentary pallidal degeneration

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 19, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000355680.11

Allele description [Variation Report for NM_001386393.1(PANK2):c.988C>T (p.Arg330Cys)]

NM_001386393.1(PANK2):c.988C>T (p.Arg330Cys)

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.988C>T (p.Arg330Cys)

HGVS:

NC_000020.11:g.3912540C>T
NG_008131.3:g.28702C>T
NM_001324191.2:c.445C>T
NM_001324193.2:c.10C>T
NM_001386393.1:c.988C>TMANE SELECT
NM_024960.6:c.445C>T
NM_153638.4:c.1318C>T
NM_153640.4:c.445C>T
NP_001311120.1:p.Arg149Cys
NP_001311122.1:p.Arg4Cys
NP_001373322.1:p.Arg330Cys
NP_079236.3:p.Arg149Cys
NP_705902.2:p.Arg440Cys
NP_705904.1:p.Arg149Cys
LRG_1016t1:c.1318C>T
LRG_1016t2:c.988C>T
LRG_1016:g.28702C>T
LRG_1016p1:p.Arg440Cys
LRG_1016p2:p.Arg330Cys
NC_000020.10:g.3893187C>T
NM_153638.2:c.1318C>T
NR_136715.2:n.889C>T

Protein change:

R149C

Links:

dbSNP: rs201329683

NCBI 1000 Genomes Browser:

rs201329683

Molecular consequence:

NM_001324191.2:c.445C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001324193.2:c.10C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001386393.1:c.988C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024960.6:c.445C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_153638.4:c.1318C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_153640.4:c.445C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_136715.2:n.889C>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000433816	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV001373361	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27303611, 33043782, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000433816

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV001373361

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 19, 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

Hallervorden-Spatz Syndrome with Seizures.

Gothwal S, Nayan S.

Basic Clin Neurosci. 2016 Apr;7(2):165-6. doi: 10.15412/J.BCN.03070210.

PubMed [citation]

PMID:: 27303611
PMCID:: PMC4892321

PANK2 p.A170fs：a novel pathogenetic mutation, compound with PANK2 p.R440P, causing pantothenate kinase Associated neurodegeneration in a Chinese family.

Yang F, Wang J, Yang Z, Ren Z, Zeng F.

Int J Neurosci. 2022 Jun;132(6):582-588. doi: 10.1080/00207454.2020.1828883. Epub 2020 Oct 14.

PubMed [citation]

PMID:: 33043782

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000433816.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001373361.5

#	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 arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 440 of the PANK2 protein (p.Arg440Cys). This variant is present in population databases (rs201329683, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 338363). 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 PANK2 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg440 amino acid residue in PANK2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27303611, 33043782). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2024

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