ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.268C>T (p.Gln90Ter)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000548.5(TSC2):c.268C>T (p.Gln90Ter)
Variation ID: 49738 Accession: VCV000049738.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2103385 (GRCh37) [ NCBI UCSC ] 16: 2053384 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Feb 14, 2024 May 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000548.5:c.268C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Gln90Ter nonsense NM_001077183.3:c.268C>T NP_001070651.1:p.Gln90Ter nonsense NM_001114382.3:c.268C>T NP_001107854.1:p.Gln90Ter nonsense NM_001318827.2:c.226-912C>T intron variant NM_001318829.2:c.121C>T NP_001305758.1:p.Gln41Ter nonsense NM_001318831.2:c.-1-2812C>T intron variant NM_001318832.2:c.301C>T NP_001305761.1:p.Gln101Ter nonsense NM_001363528.2:c.268C>T NP_001350457.1:p.Gln90Ter nonsense NM_001370404.1:c.268C>T NP_001357333.1:p.Gln90Ter nonsense NM_001370405.1:c.268C>T NP_001357334.1:p.Gln90Ter nonsense NM_021055.3:c.268C>T NP_066399.2:p.Gln90Ter nonsense NC_000016.10:g.2053384C>T NC_000016.9:g.2103385C>T NG_005895.1:g.9079C>T LRG_487:g.9079C>T LRG_487t1:c.268C>T - Protein change
- Q90*, Q41*, Q101*
- Other names
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- Canonical SPDI
- NC_000016.10:2053383:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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TSC2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10394 | 10568 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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not provided (1) |
no classification provided
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- | RCV000043003.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 20, 2023 | RCV000381969.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 23, 2020 | RCV000491603.9 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 15, 2023 | RCV000707342.16 |
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
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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
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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. |
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Pathogenic
(Jan 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329780.7
First in ClinVar: Dec 06, 2016 Last updated: May 06, 2023 |
Comment:
Identified in patients with tuberous sclerosis complex referred for genetic testing at GeneDx and in published literature (Choy 1999, Au 2007); Nonsense variant predicted to … (more)
Identified in patients with tuberous sclerosis complex referred for genetic testing at GeneDx and in published literature (Choy 1999, Au 2007); 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: 10735580, 25525159, 12111193, 16981987, 11112665, 25782670, 20633017, 17536269, 15798777, 20498439, 17304050, 32211034) (less)
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Pathogenic
(Jul 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics Inc
Accession: SCV000615894.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(Mar 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV001520799.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(May 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000836434.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49738). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49738). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 10735580, 11112665, 12111193, 16981987, 17536269, 20498439, 20633017). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln90*) 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). (less)
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Pathogenic
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002040911.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000579585.5
First in ClinVar: Jun 25, 2017 Last updated: Nov 29, 2022 |
Comment:
The p.Q90* pathogenic mutation (also known as c.268C>T), located in coding exon 3 of the TSC2 gene, results from a C to T substitution at … (more)
The p.Q90* pathogenic mutation (also known as c.268C>T), located in coding exon 3 of the TSC2 gene, results from a C to T substitution at nucleotide position 268. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This alteration has been reported in multiple unrelated individuals with clinical diagnoses of tuberous sclerosis complex (TSC) (Choy YS et al. Ann Hum Genet. 1999; 63(Pt 5):383-91; Langkau N et al. Eur J Pediatr. 2002; 161(7):393-402; Hung CC et al. BMC Med Genet. 2006; 7:72). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Jul 21, 2023)
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no assertion criteria provided
Method: research
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Tuberous sclerosis 2
Affected status: yes
Allele origin:
germline
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deCODE genetics, Amgen
Accession: SCV004022273.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_000548.5:c.268C>T (chr16:2053384) in TSC2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar … (more)
The variant NM_000548.5:c.268C>T (chr16:2053384) in TSC2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. (less)
Number of individuals with the variant: 1
Ethnicity/Population group: Icelandic
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not provided
(-)
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no classification provided
Method: curation
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TSC
Affected status: yes
Allele origin:
germline
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Tuberous sclerosis database (TSC2)
Accession: SCV000066801.3
First in ClinVar: May 04, 2013 Last updated: Sep 16, 2013 |
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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 |
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Response to everolimus is seen in TSC-associated SEGAs and angiomyolipomas independent of mutation type and site in TSC1 and TSC2. | Kwiatkowski DJ | European journal of human genetics : EJHG | 2015 | PMID: 25782670 |
Analysis of TSC cortical tubers by deep sequencing of TSC1, TSC2 and KRAS demonstrates that small second-hit mutations in these genes are rare events. | Qin W | Brain pathology (Zurich, Switzerland) | 2010 | PMID: 20633017 |
Biallelic TSC gene inactivation in tuberous sclerosis complex. | Crino PB | Neurology | 2010 | PMID: 20498439 |
[Analysis of gene mutations in two patients with tuberous sclerosis complex]. | Yuan CD | Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae | 2007 | PMID: 17536269 |
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 |
Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype--phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex. | Sancak O | European journal of human genetics : EJHG | 2005 | PMID: 15798777 |
TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/ TSC2 frequency ratios. | Langkau N | European journal of pediatrics | 2002 | PMID: 12111193 |
Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. | Dabora SL | American journal of human genetics | 2001 | PMID: 11112665 |
Superiority of denaturing high performance liquid chromatography over single-stranded conformation and conformation-sensitive gel electrophoresis for mutation detection in TSC2. | Choy YS | Annals of human genetics | 1999 | PMID: 10735580 |
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 |
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Text-mined citations for rs45517099 ...
HelpRecord last updated Feb 20, 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.