NM_013254.4(TBK1):c.349C>T (p.Arg117Ter) AND Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 8, 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:: RCV001825077.2

Allele description [Variation Report for NM_013254.4(TBK1):c.349C>T (p.Arg117Ter)]

NM_013254.4(TBK1):c.349C>T (p.Arg117Ter)

Gene:

TBK1:TANK binding kinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q14.2

Genomic location:

Preferred name:

NM_013254.4(TBK1):c.349C>T (p.Arg117Ter)

HGVS:

NC_000012.12:g.64464454C>T
NG_046906.1:g.17395C>T
NM_013254.4:c.349C>TMANE SELECT
NP_037386.1:p.Arg117Ter
LRG_1306t1:c.349C>T
LRG_1306:g.17395C>T
LRG_1306p1:p.Arg117Ter
NC_000012.11:g.64858234C>T
NM_013254.3:c.349C>T

Protein change:

R117*

Links:

dbSNP: rs757203783

NCBI 1000 Genomes Browser:

rs757203783

Molecular consequence:

NM_013254.4:c.349C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Frontotemporal dementia and/or amyotrophic lateral sclerosis 4
Synonyms:: FTDALS4
Identifiers:: MONDO: MONDO:0014641; MedGen: C4225325; Orphanet: 275872; OMIM: 616439

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002074231	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jan 12, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25700176, 25943890, 28822984, 28008748 Citation Link,
SCV004695968	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 8, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25943890, 28008748, 25803835, 26476236, 26581300, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002074231

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jan 12, 2022)

germline

clinical testing

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

Citation Link,

SCV004695968

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 8, 2023)

germline

clinical testing

PubMed (6)
[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

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, Couthouis J, Lu YF, Wang Q, Krueger BJ, Ren Z, Keebler J, Han Y, Levy SE, Boone BE, Wimbish JR, Waite LL, Jones AL, Carulli JP, Day-Williams AG, Staropoli JF, Xin WW, et al.

Science. 2015 Mar 27;347(6229):1436-41. doi: 10.1126/science.aaa3650. Epub 2015 Feb 19.

PubMed [citation]

PMID:: 25700176
PMCID:: PMC4437632

TBK1 mutations in Italian patients with amyotrophic lateral sclerosis: genetic and functional characterisation.

Pozzi L, Valenza F, Mosca L, Dal Mas A, Domi T, Romano A, Tarlarini C, Falzone YM, Tremolizzo L, Sorarù G, Cerri F, Ferraro PM, Basaia S, Agosta F, Fazio R, Comola M, Comi G, Ferrari M, Quattrini A, Lunetta C, Penco S, Bonanomi D, et al.

J Neurol Neurosurg Psychiatry. 2017 Oct;88(10):869-875. doi: 10.1136/jnnp-2017-316174. Epub 2017 Aug 19.

PubMed [citation]

PMID:: 28822984
PMCID:: PMC5629935

See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002074231.1

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

Description

Variant summary: TBK1 c.349C>T (p.Arg117X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been classified as pathogenic by our laboratory but have been reported with an associated phenotype of Amyotrophic lateral sclerosis (ALS) in the HGMD database. The variant allele was found at a frequency of 8.3e-06 in 239886 control chromosomes. c.349C>T has been reported in the literature in individuals affected with Frontotemporal Dementia And/or Amyotrophic Lateral Sclerosis (example, Cirulli_2015, Pottier_2015). At-least one of these reported cases reported a co-occurrence with another pathogenic variant(s) (OPTN c.1243-740_1612+1292delins25, p.Gly538Glufs27), suggesting an oligogenic disease mechanism (example, Pottier_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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 Invitae, SCV004695968.1

#	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1339689). This premature translational stop signal has been observed in individual(s) with frontotemporal dementia (PMID: 25943890, 28008748). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg117*) in the TBK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBK1 are known to be pathogenic (PMID: 25803835, 26476236, 26581300).

#	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: Mar 5, 2024

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