NM_022089.4(ATP13A2):c.3057del (p.Tyr1020fs) AND Kufor-Rakeb syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 7, 2020
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:: RCV000541447.9

Allele description [Variation Report for NM_022089.4(ATP13A2):c.3057del (p.Tyr1020fs)]

NM_022089.4(ATP13A2):c.3057del (p.Tyr1020fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

1p36.13

Genomic location:

Preferred name:

NM_022089.4(ATP13A2):c.3057del (p.Tyr1020fs)

Other names:

p.Tyr1020Thrfs*3

HGVS:

NC_000001.11:g.16987072del
NG_009054.1:g.29857del
NM_001141973.3:c.3042del
NM_001141974.3:c.2925del
NM_022089.4:c.3057delMANE SELECT
NP_001135445.1:p.Tyr1015fs
NP_001135446.1:p.Tyr976fs
NP_071372.1:p.Tyr1020fs
LRG_834t1:c.3057del
LRG_834:g.29857del
LRG_834p1:p.Tyr1020fs
NC_000001.10:g.17313567del
NM_022089.2:c.3057del
NM_022089.2:c.3057delC
NM_022089.3:c.3057del
NM_022089.3:c.3057delC
p.Y1020Tfs*3

Protein change:

Y1015fs

Links:

OMIM: 610513.0001; dbSNP: rs765632065

NCBI 1000 Genomes Browser:

rs765632065

Molecular consequence:

NM_001141973.3:c.3042del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001141974.3:c.2925del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_022089.4:c.3057del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000021427	OMIM	no assertion criteria provided	Pathogenic (Aug 26, 2011)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 16964263, 21724849
SCV000915371	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Apr 28, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21665991, 16964263, 21060012, 22768177 Citation Link,
SCV001432760	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 7, 2020)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000021427

OMIM

no assertion criteria provided

Pathogenic
(Aug 26, 2011)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000915371

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Likely pathogenic
(Apr 28, 2017)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001432760

Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 7, 2020)

maternal

clinical testing

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

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	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Caucasians	maternal	yes	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein.

Tan J, Zhang T, Jiang L, Chi J, Hu D, Pan Q, Wang D, Zhang Z.

J Biol Chem. 2011 Aug 26;286(34):29654-62. doi: 10.1074/jbc.M111.233874. Epub 2011 Jul 1.

PubMed [citation]

PMID:: 21724849
PMCID:: PMC3191006

Mutant Atp13a2 proteins involved in parkinsonism are degraded by ER-associated degradation and sensitize cells to ER-stress induced cell death.

Ugolino J, Fang S, Kubisch C, Monteiro MJ.

Hum Mol Genet. 2011 Sep 15;20(18):3565-77. doi: 10.1093/hmg/ddr274. Epub 2011 Jun 10.

PubMed [citation]

PMID:: 21665991
PMCID:: PMC3159557

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000021427.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a nonconsanguineous Chilean family in which 3 males and 1 female in a sibship of 11 were affected with the early-onset parkinsonism resembling that of Kufor-Rakeb syndrome (KRS; 606693), Ramirez et al. (2006) found 2 mutations of the ATP13A2 gene in compound heterozygosity. The mutation inherited from the mother was deletion of a cytosine at nucleotide position 3057 in exon 26, leading to a frameshift and stop codon after 2 extraneous amino acids (3057delC, 1019GlyfsTer1021). The second mutation, inherited from the father, was a guanine-to-adenine transition at position +5 of the donor splice site of exon 13 (1306+5G-A; 610513.0002).

By confocal analysis of human, mouse, and rat cells transfected with ATP13A2 cDNA containing the 3057C deletion, Tan et al. (2011) found that the mutant protein was not targeted to lysosomes, but was retained in the endoplasmic reticulum.

#	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 Illumina Laboratory Services, Illumina, SCV000915371.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The ATP13A2 c.3057delC (p.Tyr1020ThrfsTer3) variant is a frameshift variant and is predicted to result in a premature termination of the protein. The variant has been reported in a compound heterozygous state in four siblings of a large non-consanguineous Chilean family with Kufor-Rakeb syndrome (Ramirez et al. 2006). The variant segregates with disease in this family over two generations, with three unaffected siblings and the mother carrying the p.Tyr1020ThrfsTer3 variant in a heterozygous state. Further evaluation of this same family by Bruggemann et al. (2010) showed that the p.Tyr1020ThrfsTer3 variant in single heterozygous state may be a risk allele for later onset Parkinsonism. Control data are unavailable for this variant, which is reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregate Consortium. Functional studies demonstrated that the p.Tyr1020ThrfsTer3 variant protein is mislocalized to the endoplasmic reticulum and is targeted for degradation via the proteasome (Ramirez et al. 2006; Ugolino et al. 2011; Podhajska et al. 2012). Based on the available evidence and the potential impact of frameshift variants, the p.Tyr1020ThrfsTer3 variant is classified as likely pathogenic for Kufor-Rakeb syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV001432760.1

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

Description

The c.3057delC variant has been previously reported as disease-causing in PMIDs 22296644, 21724849, 29966207, 16964263, 21665991.

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

Last Updated: Nov 30, 2024

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