NM_001386393.1(PANK2):c.740G>C (p.Arg247Pro) AND Pigmentary pallidal degeneration

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000990272.11

Allele description [Variation Report for NM_001386393.1(PANK2):c.740G>C (p.Arg247Pro)]

NM_001386393.1(PANK2):c.740G>C (p.Arg247Pro)

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.740G>C (p.Arg247Pro)

HGVS:

NC_000020.11:g.3910665G>C
NG_008131.3:g.26827G>C
NM_001324191.2:c.197G>C
NM_001324193.2:c.-239G>C
NM_001386393.1:c.740G>CMANE SELECT
NM_024960.6:c.197G>C
NM_153638.4:c.1070G>C
NM_153640.4:c.197G>C
NP_001311120.1:p.Arg66Pro
NP_001373322.1:p.Arg247Pro
NP_079236.3:p.Arg66Pro
NP_705902.2:p.Arg357Pro
NP_705904.1:p.Arg66Pro
LRG_1016t1:c.1070G>C
LRG_1016t2:c.740G>C
LRG_1016:g.26827G>C
LRG_1016p1:p.Arg357Pro
LRG_1016p2:p.Arg247Pro
NC_000020.10:g.3891312G>C
NM_153638.2:c.1070G>C
NM_153638.3:c.1070G>C
NR_136715.2:n.641G>C

Protein change:

R247P

Links:

dbSNP: rs754521581

NCBI 1000 Genomes Browser:

rs754521581

Molecular consequence:

NM_001324193.2:c.-239G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001324191.2:c.197G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001386393.1:c.740G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_024960.6:c.197G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_153638.4:c.1070G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_153640.4:c.197G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_136715.2:n.641G>C - 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
SCV001141200	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001391682	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 17, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15911822, 16437574, 22221393, 28680084, 28492532
SCV002599022	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Sep 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001141200

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Likely pathogenic
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV001391682

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 17, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002599022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Sep 22, 2022)

germline

clinical testing

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

Citation Link

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation.

Hartig MB, Hörtnagel K, Garavaglia B, Zorzi G, Kmiec T, Klopstock T, Rostasy K, Svetel M, Kostic VS, Schuelke M, Botz E, Weindl A, Novakovic I, Nardocci N, Prokisch H, Meitinger T.

Ann Neurol. 2006 Feb;59(2):248-56.

PubMed [citation]

PMID:: 16437574

Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations.

Leoni V, Strittmatter L, Zorzi G, Zibordi F, Dusi S, Garavaglia B, Venco P, Caccia C, Souza AL, Deik A, Clish CB, Rimoldi M, Ciusani E, Bertini E, Nardocci N, Mootha VK, Tiranti V.

Mol Genet Metab. 2012 Mar;105(3):463-71. doi: 10.1016/j.ymgme.2011.12.005. Epub 2011 Dec 14.

PubMed [citation]

PMID:: 22221393
PMCID:: PMC3487396

See all PubMed Citations (5)

Details of each submission

From Mendelics, SCV001141200.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001391682.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 357 of the PANK2 protein (p.Arg357Pro). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of neurodegeneration with brain iron accumulation (PMID: 15911822; Invitae). This variant is also known as c.G740C, p.R247P. ClinVar contains an entry for this variant (Variation ID: 803594). 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. This variant disrupts the p.Arg357 amino acid residue in PANK2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16437574, 22221393, 28680084). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002599022.1

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

Description

Variant summary: PANK2 c.1070G>C (p.Arg357Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251366 control chromosomes. c.1070G>C has been reported in the literature in individuals affected with Pantothenate Kinase-Associated Neurodegeneration (Pelleccia_2005). These data indicate that the variant is likely to be associated with disease. Additionally, two other variants at the same codon have been reported in association with Pantothenate kinase-associated neurodegeneration in HGMD (R357Q, R357W), supporting pathogenicity. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one classified the variant as uncertain significance. Based on the evidence outlined above, the variant was 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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