VCV002663128.2 - ClinVar

NM_001386393.1(PANK2):c.1061C>G (p.Pro354Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001386393.1(PANK2):c.1061C>G (p.Pro354Arg)

Variation ID: 2663128 Accession: VCV002663128.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20p13 20: 3912613 (GRCh38) [ NCBI UCSC ] 20: 3893260 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 25, 2023	Feb 14, 2024	Oct 14, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001386393.1:c.1061C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001373322.1:p.Pro354Arg	missense
NM_001324191.2:c.518C>G	NP_001311120.1:p.Pro173Arg	missense
NM_001324193.2:c.83C>G	NP_001311122.1:p.Pro28Arg	missense
NM_024960.6:c.518C>G	NP_079236.3:p.Pro173Arg	missense
NM_153638.4:c.1391C>G	NP_705902.2:p.Pro464Arg	missense
NM_153640.4:c.518C>G	NP_705904.1:p.Pro173Arg	missense
NR_136715.2:n.962C>G		non-coding transcript variant
NC_000020.11:g.3912613C>G
NC_000020.10:g.3893260C>G
NG_008131.3:g.28775C>G
LRG_1016:g.28775C>G
LRG_1016t1:c.1391C>G	LRG_1016p1:p.Pro464Arg
LRG_1016t2:c.1061C>G	LRG_1016p2:p.Pro354Arg

... more HGVS ... less HGVS

Protein change

P173R, P28R, P354R, P464R

Other names

Canonical SPDI

NC_000020.11:3912612:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PANK2		-	-	GRCh38 GRCh37	481	748

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Likely pathogenic (1)	criteria provided, single submitter	May 10, 2023	RCV003442316.1
Pigmentary pallidal degeneration	Pathogenic (1)	criteria provided, single submitter	Oct 14, 2023	RCV003502735.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (May 10, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004169827.1 First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023	Comment: Observed with a pathogenic variant in unrelated patients with features of PANK2-related neurodegeneration referred for genetic testing at GeneDx and in published literature, but it … (more) Observed with a pathogenic variant in unrelated patients with features of PANK2-related neurodegeneration referred for genetic testing at GeneDx and in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Egan et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31540697, 16023068) (less)
Pathogenic (Oct 14, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Pigmentary pallidal degeneration Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004298021.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 16023068 Comment: This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 464 of the PANK2 protein (p.Pro464Arg). … (more) This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 464 of the PANK2 protein (p.Pro464Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pantothenate kinase-associated neurodegeneration (PMID: 16023068). 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. This variant is also known as 1061C>G. 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. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

Observed with a pathogenic variant in unrelated patients with features of PANK2-related neurodegeneration referred for genetic testing at GeneDx and in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Egan et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31540697, 16023068)

Comment:

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 464 of the PANK2 protein (p.Pro464Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pantothenate kinase-associated neurodegeneration (PMID: 16023068). 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. This variant is also known as 1061C>G. 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. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome).	Egan RA	American journal of ophthalmology	2005	PMID: 16023068

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001386393.1(PANK2):c.1061C>G (p.Pro354Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...