ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.4846C>T (p.Gln1616Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(5); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000548.5(TSC2):c.4846C>T (p.Gln1616Ter)
Variation ID: 49326 Accession: VCV000049326.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.3 16: 2086376 (GRCh38) [ NCBI UCSC ] 16: 2136377 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 16, 2013 Jul 15, 2024 Mar 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000548.5:c.4846C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Gln1616Ter nonsense NM_000548.4:c.4846C>T NM_001077183.3:c.4645C>T NP_001070651.1:p.Gln1549Ter nonsense NM_001114382.3:c.4777C>T NP_001107854.1:p.Gln1593Ter nonsense NM_001318827.2:c.4537C>T NP_001305756.1:p.Gln1513Ter nonsense NM_001318829.2:c.4501C>T NP_001305758.1:p.Gln1501Ter nonsense NM_001318831.2:c.4114C>T NP_001305760.1:p.Gln1372Ter nonsense NM_001318832.2:c.4678C>T NP_001305761.1:p.Gln1560Ter nonsense NM_001363528.2:c.4648C>T NP_001350457.1:p.Gln1550Ter nonsense NM_001370404.1:c.4714C>T NP_001357333.1:p.Gln1572Ter nonsense NM_001370405.1:c.4717C>T NP_001357334.1:p.Gln1573Ter nonsense NM_021055.3:c.4717C>T NP_066399.2:p.Gln1573Ter nonsense NC_000016.10:g.2086376C>T NC_000016.9:g.2136377C>T NG_005895.1:g.42071C>T LRG_487:g.42071C>T LRG_487t1:c.4846C>T - Protein change
- Q1616*, Q1501*, Q1513*, Q1549*, Q1573*, Q1593*, Q1560*, Q1372*, Q1550*, Q1572*
- Other names
- -
- Canonical SPDI
- NC_000016.10:2086375:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
TSC2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10660 | 10854 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
not provided (1) |
no classification provided
|
- | RCV000042586.4 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Mar 25, 2024 | RCV000470698.8 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 22, 2022 | RCV001091866.22 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002041006.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
|
|
Pathogenic
(Aug 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248123.23
First in ClinVar: May 12, 2020 Last updated: Jul 15, 2024 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Dec 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002770201.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32055024, 16981987) (less)
|
|
Pathogenic
(Oct 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003800460.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The TSC2 c.4846C>T; p.Gln1616Ter variant (rs45455296) is reported in the literature in an individual affected with tuberous sclerosis (Hung 2006). This variant is reported in … (more)
The TSC2 c.4846C>T; p.Gln1616Ter variant (rs45455296) is reported in the literature in an individual affected with tuberous sclerosis (Hung 2006). This variant is reported in ClinVar (Variation ID: 49326) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. In vitro and in vivo functional analyses demonstrate that loss of the TSC2 GAP domain function, where the p.Gln1616Ter variant lies, prevents TSC2 activity (Fu 2013, Hansmann 2020). Additionally, upstream and downstream truncating variants have been described in individuals with tuberous sclerosis and are considered to be pathogenic (Maheshwar 1997). Based on available information, this variant is considered to be pathogenic. References: Fu C et al. Conditional and domain-specific inactivation of the Tsc2 gene in neural progenitor cells. Genesis. 2013 Apr;51(4):284-92. PMID: 23359422 Hansmann P et al. Structure of the TSC2 GAP Domain: Mechanistic Insight into Catalysis and Pathogenic Mutations. Structure. 2020 Aug 4;28(8):933-942.e4. PMID: 32502382 Hung CC et al. Molecular and clinical analyses of 84 patients with tuberous sclerosis complex. BMC Med Genet. 2006 Sep 18;7:72. PMID: 16981987 Maheshwar MM et al. The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis. Hum Mol Genet. 1997 Oct;6(11):1991-6. PMID: 9302281 (less)
|
|
Pathogenic
(Oct 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000544319.5
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln1616*) in the TSC2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln1616*) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 16981987). ClinVar contains an entry for this variant (Variation ID: 49326). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Uncertain significance
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806093.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
not provided
(-)
|
no classification provided
Method: curation
|
TSC
Affected status: yes
Allele origin:
germline
|
Tuberous sclerosis database (TSC2)
Accession: SCV000066380.3
First in ClinVar: May 04, 2013 Last updated: Sep 16, 2013 |
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. | Au KS | Genetics in medicine : official journal of the American College of Medical Genetics | 2007 | PMID: 17304050 |
Molecular and clinical analyses of 84 patients with tuberous sclerosis complex. | Hung CC | BMC medical genetics | 2006 | PMID: 16981987 |
Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. | Jones AC | American journal of human genetics | 1999 | PMID: 10205261 |
Text-mined citations for rs45455296 ...
HelpRecord last updated Jul 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.