NM_032409.3(PINK1):c.1366C>T (p.Gln456Ter) AND Autosomal recessive early-onset Parkinson disease 6

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 13, 2022
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:: RCV000002516.8

Allele description [Variation Report for NM_032409.3(PINK1):c.1366C>T (p.Gln456Ter)]

NM_032409.3(PINK1):c.1366C>T (p.Gln456Ter)

Genes:

PINK1-AS:PINK1 antisense RNA [Gene - HGNC]
PINK1:PTEN induced kinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.12

Genomic location:

Preferred name:

NM_032409.3(PINK1):c.1366C>T (p.Gln456Ter)

HGVS:

NC_000001.11:g.20649109C>T
NG_008164.1:g.20655C>T
NM_032409.3:c.1366C>TMANE SELECT
NP_115785.1:p.Gln456Ter
NC_000001.10:g.20975602C>T
NM_032409.2:c.1366C>T
NR_046507.1:n.3085G>A

Protein change:

Q456*; GLN456TER

Links:

OMIM: 608309.0012; dbSNP: rs45539432

NCBI 1000 Genomes Browser:

rs45539432

Molecular consequence:

NR_046507.1:n.3085G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_032409.3:c.1366C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Autosomal recessive early-onset Parkinson disease 6 (PARK6)
Synonyms:: PARKINSON DISEASE 6, EARLY-ONSET; PARKINSON DISEASE 6, MODIFIER OF; PINK1-Related Parkinson Disease
Identifiers:: MONDO: MONDO:0011613; MedGen: C1853833; Orphanet: 2828; OMIM: 605909

Recent activity

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olfactory receptor 5V1 [Chrysemys picta bellii]
olfactory receptor 5V1 [Chrysemys picta bellii]
gi|641783630|ref|XP_008174183.1|

Protein
Related DataSets for GEO Profiles (Select 131526901) (1)
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Accession: GDS5816

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022674	OMIM	no assertion criteria provided	Pathogenic (Sep 16, 2008)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 16769864, 18685134
SCV002234956	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 13, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16769864, 18685134, 28502045, 15087508, 15349870, 28492532
SCV002574802	GeneReviews	no classification provided	not provided	germline	literature only

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000022674

OMIM

no assertion criteria provided

Pathogenic
(Sep 16, 2008)

germline

literature only

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

SCV002234956

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 13, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002574802

GeneReviews

no classification provided

not provided

germline

literature only

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	literature only, clinical testing

Citations

PubMed

Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?

Hedrich K, Hagenah J, Djarmati A, Hiller A, Lohnau T, Lasek K, Grünewald A, Hilker R, Steinlechner S, Boston H, Kock N, Schneider-Gold C, Kress W, Siebner H, Binkofski F, Lencer R, Münchau A, Klein C.

Arch Neurol. 2006 Jun;63(6):833-8.

PubMed [citation]

PMID:: 16769864

PINK1 mutations and parkinsonism.

Ishihara-Paul L, Hulihan MM, Kachergus J, Upmanyu R, Warren L, Amouri R, Elango R, Prinjha RK, Soto A, Kefi M, Zouari M, Sassi SB, Yahmed SB, El Euch-Fayeche G, Matthews PM, Middleton LT, Gibson RA, Hentati F, Farrer MJ.

Neurology. 2008 Sep 16;71(12):896-902. doi: 10.1212/01.wnl.0000323812.40708.1f. Epub 2008 Aug 6.

PubMed [citation]

PMID:: 18685134
PMCID:: PMC2676945

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000022674.3

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

Description

In 4 affected sibs of a large German family with early-onset parkinsonism (PARK6; 605909), Hedrich et al. (2006) identified a homozygous 1366C-T transition in exon 7 of the PINK1 gene, resulting in a gln456-to-ter (Q456X) substitution. Six heterozygous offspring of the homozygous patients were found to have subtle signs of disease, and 5 heterozygous offspring were considered to be unaffected. The 6 affected heterozygous offspring were not aware of their signs, but clinical examination showed unilaterally reduced or absent arm swing and rigidity. Hedrich et al. (2006) concluded that heterozygous PINK1 mutations confer susceptibility to the development of PD. Of clinical note, parkinsonian signs were more marked on the dominant right-hand side in all mutation carriers, and 10 of 15 mutation carriers had psychiatric disturbances.

Ishihara-Paul et al. (2008) identified homozygosity for the Q456X mutation in 7 (7.8%) of 92 Tunisian families with Parkinson disease and in 5 (2.1%) of 240 patients with no family history of PD. There was no evidence that heterozygosity for the mutation contributed to development of PD.

#	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 Invitae, SCV002234956.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2415). This premature translational stop signal has been observed in individual(s) with early-onset Parkinson disease (PMID: 16769864, 18685134, 28502045). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs45539432, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Gln456*) in the PINK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PINK1 are known to be pathogenic (PMID: 15087508, 15349870).

#	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 GeneReviews, SCV002574802.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	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: Feb 20, 2024

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