NM_022089.4(ATP13A2):c.1510G>C (p.Gly504Arg) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 14, 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:: RCV001851533.3

Allele description [Variation Report for NM_022089.4(ATP13A2):c.1510G>C (p.Gly504Arg)]

NM_022089.4(ATP13A2):c.1510G>C (p.Gly504Arg)

Gene:

ATP13A2:ATPase cation transporting 13A2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.13

Genomic location:

Preferred name:

NM_022089.4(ATP13A2):c.1510G>C (p.Gly504Arg)

HGVS:

NC_000001.11:g.16996008C>G
NG_009054.1:g.20921G>C
NM_001141973.3:c.1495G>C
NM_001141974.3:c.1495G>C
NM_022089.4:c.1510G>CMANE SELECT
NP_001135445.1:p.Gly499Arg
NP_001135446.1:p.Gly499Arg
NP_071372.1:p.Gly504Arg
LRG_834t1:c.1510G>C
LRG_834:g.20921G>C
LRG_834p1:p.Gly504Arg
NC_000001.10:g.17322503C>G
Q9NQ11:p.Gly504Arg

Protein change:

G499R; GLY504ARG

Links:

UniProtKB: Q9NQ11#VAR_058455; OMIM: 610513.0004; dbSNP: rs121918227

NCBI 1000 Genomes Browser:

rs121918227

Molecular consequence:

NM_001141973.3:c.1495G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001141974.3:c.1495G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_022089.4:c.1510G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Kufor-Rakeb syndrome (KRS)
Synonyms:: Park 9; Pallidopyramidal degeneration with supranuclear upgaze paresis, and dementia; PARKINSON DISEASE 9, AUTOSOMAL RECESSIVE, JUVENILE-ONSET
Identifiers:: MONDO: MONDO:0011706; MedGen: C1847640; Orphanet: 306674; Orphanet: 314632; OMIM: 606693

Name:: Autosomal recessive spastic paraplegia type 78
Identifiers:: MONDO: MONDO:0014975; MedGen: C5567893; OMIM: 617225

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002262684	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 14, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22768177, 22847264, 23499937, 17485642, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002262684

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 14, 2023)

germline

clinical testing

PubMed (5)
[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

Common pathogenic effects of missense mutations in the P-type ATPase ATP13A2 (PARK9) associated with early-onset parkinsonism.

Podhajska A, Musso A, Trancikova A, Stafa K, Moser R, Sonnay S, Glauser L, Moore DJ.

PLoS One. 2012;7(6):e39942. doi: 10.1371/journal.pone.0039942. Epub 2012 Jun 29.

PubMed [citation]

PMID:: 22768177
PMCID:: PMC3386943

Characterization of cellular protective effects of ATP13A2/PARK9 expression and alterations resulting from pathogenic mutants.

Covy JP, Waxman EA, Giasson BI.

J Neurosci Res. 2012 Dec;90(12):2306-16. doi: 10.1002/jnr.23112. Epub 2012 Jul 30.

PubMed [citation]

PMID:: 22847264
PMCID:: PMC4484830

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV002262684.3

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

Description

Experimental studies have shown that this missense change affects ATP13A2 function (PMID: 22768177, 22847264, 23499937). 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. 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 not expected to disrupt ATP13A2 protein function. ClinVar contains an entry for this variant (Variation ID: 1221). This missense change has been observed in individuals with clinical features of Kufor-Rakeb syndrome or hereditary spastic paraplegia (PMID: 17485642; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 504 of the ATP13A2 protein (p.Gly504Arg).

#	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: Jun 17, 2024

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