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: 10533067, 25525159, 28178598, 21520333, 32211034, 35007768)
ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.4507C>T (p.Gln1503Ter)
Germline
Classification
Help
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.
(8)
Help
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000548.5(TSC2):c.4507C>T (p.Gln1503Ter)
Variation ID: 49301 Accession: VCV000049301.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2084964 (GRCh38) [ NCBI UCSC ] 16: 2134965 (GRCh37) [ 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 May 1, 2024 Jun 30, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000548.5:c.4507C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Gln1503Ter nonsense NM_001077183.3:c.4306C>T NP_001070651.1:p.Gln1436Ter nonsense NM_001114382.3:c.4438C>T NP_001107854.1:p.Gln1480Ter nonsense NM_001318827.2:c.4198C>T NP_001305756.1:p.Gln1400Ter nonsense NM_001318829.2:c.4162C>T NP_001305758.1:p.Gln1388Ter nonsense NM_001318831.2:c.3775C>T NP_001305760.1:p.Gln1259Ter nonsense NM_001318832.2:c.4339C>T NP_001305761.1:p.Gln1447Ter nonsense NM_001363528.2:c.4309C>T NP_001350457.1:p.Gln1437Ter nonsense NM_001370404.1:c.4375C>T NP_001357333.1:p.Gln1459Ter nonsense NM_001370405.1:c.4378C>T NP_001357334.1:p.Gln1460Ter nonsense NM_021055.3:c.4378C>T NP_066399.2:p.Gln1460Ter nonsense NC_000016.10:g.2084964C>T NC_000016.9:g.2134965C>T NG_005895.1:g.40659C>T LRG_487:g.40659C>T LRG_487t1:c.4507C>T - Protein change
- Q1503*, Q1259*, Q1447*, Q1459*, Q1460*, Q1388*, Q1400*, Q1480*, Q1436*, Q1437*
- Other names
- -
- Canonical SPDI
- NC_000016.10:2084963: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
Help
The frequency of the allele represented by this VCV record.
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- Links
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. |
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| TSC2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10745 | 10944 | |
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
|
- | RCV000042560.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 12, 2023 | RCV000627231.2 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 23, 2023 | RCV000553662.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 4, 2022 | RCV002477138.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 30, 2023 | RCV003380406.2 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Feb 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000748220.3
First in ClinVar: May 21, 2018 Last updated: Feb 18, 2023 |
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: 10533067, 25525159, 28178598, 21520333, 32211034, 35007768) (less)
|
|
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Pathogenic
(Apr 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000644541.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln1503*) 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.Gln1503*) 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 (PMID: 10533067, 21520333, 28178598). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49301). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004098174.2
First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024 |
Comment:
The p.Q1503* pathogenic mutation (also known as c.4507C>T), located in coding exon 34 of the TSC2 gene, results from a C to T substitution at … (more)
The p.Q1503* pathogenic mutation (also known as c.4507C>T), located in coding exon 34 of the TSC2 gene, results from a C to T substitution at nucleotide position 4507. This changes the amino acid from a glutamine to a stop codon within coding exon 34. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TSC2-related disease (Ambry internal data; Niida Y et al. Hum Mutat, 1999;14:412-22; Yu T et al. Clin Neurol Neurosurg, 2017 Mar;154:104-108). This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with tuberous sclerosis complex (TSC) (Ding Y et al. Front Genet, 2020 Mar;11:204). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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)
|
|
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Pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002040998.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
|
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Pathogenic
(Feb 04, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Lymphangiomyomatosis
Isolated focal cortical dysplasia type II Tuberous sclerosis 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002796068.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV004013509.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is predicted to result in a loss or disruption of normal protein function … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000049301 / PMID: 10533067). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cortical tubers (present) , Kidney angiomyolipoma (present) , Shagreen patch (present)
|
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Pathogenic
(Jun 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175237.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The TSC2 c.4507C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) The TSC2 c.4507C>T variant is a single nucleotide change which is predicted to result … (more)
The TSC2 c.4507C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) The TSC2 c.4507C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 1503. The variant has been previously reported in individuals with a clinical presentation of Tuberous sclerosis (PMID:10533067, PMID:25525159, PMID:32211034.) (PS4_Moderate). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs45517348) and in the HGMD database: CM992689. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 49301). (less)
|
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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
|
Tuberous sclerosis database (TSC2)
Accession: SCV000066354.3
First in ClinVar: May 04, 2013 Last updated: Sep 16, 2013 |
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Gln1503*) 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 (PMID: 10533067, 21520333, 28178598). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49301). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Q1503* pathogenic mutation (also known as c.4507C>T), located in coding exon 34 of the TSC2 gene, results from a C to T substitution at nucleotide position 4507. This changes the amino acid from a glutamine to a stop codon within coding exon 34. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TSC2-related disease (Ambry internal data; Niida Y et al. Hum Mutat, 1999;14:412-22; Yu T et al. Clin Neurol Neurosurg, 2017 Mar;154:104-108). This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with tuberous sclerosis complex (TSC) (Ding Y et al. Front Genet, 2020 Mar;11:204). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000049301 / PMID: 10533067). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The TSC2 c.4507C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) The TSC2 c.4507C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 1503. The variant has been previously reported in individuals with a clinical presentation of Tuberous sclerosis (PMID:10533067, PMID:25525159, PMID:32211034.) (PS4_Moderate). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs45517348) and in the HGMD database: CM992689. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 49301).
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. |
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 disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10533067, 25525159, 28178598, 21520333, 32211034, 35007768)
Comment:
This sequence change creates a premature translational stop signal (p.Gln1503*) 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 (PMID: 10533067, 21520333, 28178598). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49301). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Q1503* pathogenic mutation (also known as c.4507C>T), located in coding exon 34 of the TSC2 gene, results from a C to T substitution at nucleotide position 4507. This changes the amino acid from a glutamine to a stop codon within coding exon 34. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TSC2-related disease (Ambry internal data; Niida Y et al. Hum Mutat, 1999;14:412-22; Yu T et al. Clin Neurol Neurosurg, 2017 Mar;154:104-108). This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with tuberous sclerosis complex (TSC) (Ding Y et al. Front Genet, 2020 Mar;11:204). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000049301 / PMID: 10533067). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The TSC2 c.4507C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) The TSC2 c.4507C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 1503. The variant has been previously reported in individuals with a clinical presentation of Tuberous sclerosis (PMID:10533067, PMID:25525159, PMID:32211034.) (PS4_Moderate). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs45517348) and in the HGMD database: CM992689. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 49301).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genotype and Phenotype Analysis of Chinese Children With Tuberous Sclerosis Complex: A Pediatric Cohort Study. | Ding Y | Frontiers in genetics | 2020 | PMID: 32211034 |
| Novel TSC1 and TSC2 gene mutations in Chinese patients with tuberous sclerosis complex. | Yu T | Clinical neurology and neurosurgery | 2017 | PMID: 28178598 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
| 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 |
| Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis. | Niida Y | Human mutation | 1999 | PMID: 10533067 |
| 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 rs45517348 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.