NM_198578.4(LRRK2):c.7067C>T (p.Thr2356Ile) AND Autosomal dominant Parkinson disease 8

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Dec 26, 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:: RCV000032506.10

Allele description

NM_198578.4(LRRK2):c.7067C>T (p.Thr2356Ile)

Gene:

LRRK2:leucine rich repeat kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q12

Genomic location:

Preferred name:

NM_198578.4(LRRK2):c.7067C>T (p.Thr2356Ile)

HGVS:

NC_000012.12:g.40363440C>T
NG_011709.1:g.143430C>T
NM_198578.4:c.7067C>TMANE SELECT
NP_940980.4:p.Thr2356Ile
NC_000012.11:g.40757242C>T
NM_198578.3:c.7067C>T
Q5S007:p.Thr2356Ile

Protein change:

T2356I

Links:

UniProtKB: Q5S007#VAR_024963; dbSNP: rs113511708

NCBI 1000 Genomes Browser:

rs113511708

Molecular consequence:

NM_198578.4:c.7067C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal dominant Parkinson disease 8
Synonyms:: Parkinson disease 8; Parkinson disease 8, susceptibility to; LRRK2-Related Parkinson Disease
Identifiers:: MONDO: MONDO:0011764; MedGen: C1846862; Orphanet: 411602; OMIM: 607060

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000056169	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (1) [See all records that cite this PMID]
SCV001138696	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001366858	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 1, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002262018	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 26, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17419834, 17622782, 18973254, 21885347, 17447891, 20642453, 35950872, 28492532

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Summary from all submissions

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

Citations

PubMed

LRRK2 Parkinson Disease.

Saunders-Pullman R, Raymond D, Elango S.

2006 Nov 2 [updated 2023 Jul 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301387

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (10)

Details of each submission

From GeneReviews, SCV000056169.2

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

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

From Mendelics, SCV001138696.1

#	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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001366858.2

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

Description

This variant was classified as: Uncertain significance.

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

From Invitae, SCV002262018.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2356 of the LRRK2 protein (p.Thr2356Ile). This variant is present in population databases (rs113511708, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson disease and in healthy individuals (PMID: 17419834, 17622782, 18973254, 21885347). ClinVar contains an entry for this variant (Variation ID: 39232). 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 LRRK2 protein function. Experimental studies have shown that this missense change does not substantially affect LRRK2 function (PMID: 17447891, 20642453, 35950872). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Aug 4, 2024

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