NM_001163435.3(TBCK):c.1363A>T (p.Lys455Ter) AND TBCK-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 16, 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:: RCV003335232.2

Allele description [Variation Report for NM_001163435.3(TBCK):c.1363A>T (p.Lys455Ter)]

NM_001163435.3(TBCK):c.1363A>T (p.Lys455Ter)

Gene:

TBCK:TBC1 domain containing kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q24

Genomic location:

Preferred name:

NM_001163435.3(TBCK):c.1363A>T (p.Lys455Ter)

Other names:

TBCK, LYS455TER (rs376699648)

HGVS:

NC_000004.12:g.106235355T>A
NG_034057.3:g.86329A>T
NM_001163435.3:c.1363A>TMANE SELECT
NM_001163436.4:c.1363A>T
NM_001163437.3:c.1246A>T
NM_001290768.2:c.847A>T
NM_033115.5:c.1174A>T
NP_001156907.2:p.Lys455Ter
NP_001156908.2:p.Lys455Ter
NP_001156909.2:p.Lys416Ter
NP_001277697.2:p.Lys283Ter
NP_149106.3:p.Lys392Ter
LRG_836t1:c.1363A>T
LRG_836:g.86329A>T
LRG_836p1:p.Lys455Ter
NC_000004.11:g.107156512T>A
NG_034057.2:g.91141A>T
NM_001163435.2:c.1363A>T

Protein change:

K283*; LYS455TER

Links:

OMIM: 616899.0003; dbSNP: rs376699648

NCBI 1000 Genomes Browser:

rs376699648

Molecular consequence:

NM_001163435.3:c.1363A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001163436.4:c.1363A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001163437.3:c.1246A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001290768.2:c.847A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_033115.5:c.1174A>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: TBCK-related disorder
Synonyms:: TBCK-related disorders; TBCK-related condition
Identifiers:

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004046394	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004112085	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 16, 2023)	germline	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

SCV004046394

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

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

SCV004112085

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 16, 2023)

germline

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	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

Citations

PubMed

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

Details of each submission

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046394.1

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

Description

This nonsense variant found in exon 16 of 27 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a homozygous change in patients with TBCK-related disorders (PMID: 27040692). Loss-of-function variation in the TBCK gene is an established mechanism of disease (ClinVar, HGMD). The c.1363A>T (p.Lys455Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/244480) and absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.1363A>T (p.Lys455Ter) variant is classified as Pathogenic.

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

From PreventionGenetics, part of Exact Sciences, SCV004112085.1

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

Description

The TBCK c.1363A>T variant is predicted to result in premature protein termination (p.Lys455*). This variant was reported in a consanguineous family in the homozygous state in two individuals with severe infantile syndromic encephalopathy (Chong et al 2016. PubMed ID: 27040692). This variant is reported in 0.0089% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-107156512-T-A). Nonsense variants in TBCK are expected to be pathogenic. This variant is interpreted as 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

Last Updated: Nov 3, 2024

ClinVar

Relating variation to medicine