The c.3206_3207delTG pathogenic mutation, located in coding exon 27 of the TSC2 gene, results from a deletion of two nucleotides at nucleotide positions 3206 to 3207, causing a translational frameshift with a predicted alternate stop codon (p.V1069Dfs*98). This alteration was detected in one individual who fulfilled diagnostic criteria for Tuberous Sclerosis Complex (TSC) (Langkau N et al. Eur. J. Pediatr., 2002 Jul;161:393-402) and as a de novo occurrence in an infant with seizures and hypomelanotic macules (Li W et al. J. Neurogenet. Oct;30:285-287). 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.
ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.3206_3207del (p.Val1069fs)
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.3206_3207del (p.Val1069fs)
Variation ID: 49246 Accession: VCV000049246.23
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 16p13.3 16: 2079348-2079349 (GRCh38) [ NCBI UCSC ] 16: 2129349-2129350 (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 Oct 20, 2024 Dec 5, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000548.5:c.3206_3207del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Val1069fs frameshift NM_000548.3:c.3206_3207delTG NM_001077183.3:c.3074_3075del NP_001070651.1:p.Val1025fs frameshift NM_001114382.3:c.3206_3207del NP_001107854.1:p.Val1069fs frameshift NM_001318827.2:c.2966_2967del NP_001305756.1:p.Val989fs frameshift NM_001318829.2:c.2930_2931del NP_001305758.1:p.Val977fs frameshift NM_001318831.2:c.2474_2475del NP_001305760.1:p.Val825fs frameshift NM_001318832.2:c.3107_3108del NP_001305761.1:p.Val1036fs frameshift NM_001363528.2:c.3077_3078del NP_001350457.1:p.Val1026fs frameshift NM_001370404.1:c.3074_3075del NP_001357333.1:p.Val1025fs frameshift NM_001370405.1:c.3077_3078del NP_001357334.1:p.Val1026fs frameshift NM_021055.3:c.3077_3078del NP_066399.2:p.Val1026fs frameshift NC_000016.10:g.2079348TG[1] NC_000016.9:g.2129349TG[1] NG_005895.1:g.35043TG[1] LRG_487:g.35043TG[1] - Protein change
- V1026fs, V825fs, V1025fs, V1036fs, V989fs, V1069fs, V977fs
- Other names
- -
- Canonical SPDI
- NC_000016.10:2079347:TGTG:TG
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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.
- -
- 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. |
|||
| TSC2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10758 | 10957 | |
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
|
- | RCV000042505.3 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 5, 2023 | RCV000201154.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2023 | RCV000727088.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 14, 2018 | RCV002321535.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 14, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002610400.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.3206_3207delTG pathogenic mutation, located in coding exon 27 of the TSC2 gene, results from a deletion of two nucleotides at nucleotide positions 3206 to … (more)
The c.3206_3207delTG pathogenic mutation, located in coding exon 27 of the TSC2 gene, results from a deletion of two nucleotides at nucleotide positions 3206 to 3207, causing a translational frameshift with a predicted alternate stop codon (p.V1069Dfs*98). This alteration was detected in one individual who fulfilled diagnostic criteria for Tuberous Sclerosis Complex (TSC) (Langkau N et al. Eur. J. Pediatr., 2002 Jul;161:393-402) and as a de novo occurrence in an infant with seizures and hypomelanotic macules (Li W et al. J. Neurogenet. Oct;30:285-287). 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)
|
|
|
Pathogenic
(Jul 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033430.11
First in ClinVar: Sep 16, 2023 Last updated: Oct 20, 2024 |
Comment:
TSC2: PVS1, PM2, PS4:Moderate
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jun 14, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000255890.2
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015 |
|
|
|
Pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002040969.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
|
|
|
Pathogenic
(Dec 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003441711.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val1069Aspfs*98) 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.Val1069Aspfs*98) 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: 12111193). This variant is also known as 3224-3225delTG. ClinVar contains an entry for this variant (Variation ID: 49246). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Feb 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000705518.2
First in ClinVar: Oct 19, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
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Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572983.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift 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. Frameshift 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: VCV000049246 / PMID: 12111193). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Seizure (present) , Cognitive impairment (present) , Mixed hypo- and hyperpigmentation of the skin (present)
|
|
|
not provided
(-)
|
no classification provided
Method: curation
|
TSC
Affected status: yes
Allele origin:
germline
|
Tuberous sclerosis database (TSC2)
Accession: SCV000066296.3
First in ClinVar: May 04, 2013 Last updated: Sep 16, 2013 |
|
Comment:
Comment:
TSC2: PVS1, PM2, PS4:Moderate
Comment:
This sequence change creates a premature translational stop signal (p.Val1069Aspfs*98) 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: 12111193). This variant is also known as 3224-3225delTG. ClinVar contains an entry for this variant (Variation ID: 49246). For these reasons, this variant has been classified as Pathogenic.
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift 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: VCV000049246 / PMID: 12111193). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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:
The c.3206_3207delTG pathogenic mutation, located in coding exon 27 of the TSC2 gene, results from a deletion of two nucleotides at nucleotide positions 3206 to 3207, causing a translational frameshift with a predicted alternate stop codon (p.V1069Dfs*98). This alteration was detected in one individual who fulfilled diagnostic criteria for Tuberous Sclerosis Complex (TSC) (Langkau N et al. Eur. J. Pediatr., 2002 Jul;161:393-402) and as a de novo occurrence in an infant with seizures and hypomelanotic macules (Li W et al. J. Neurogenet. Oct;30:285-287). 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:
TSC2: PVS1, PM2, PS4:Moderate
Comment:
This sequence change creates a premature translational stop signal (p.Val1069Aspfs*98) 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: 12111193). This variant is also known as 3224-3225delTG. ClinVar contains an entry for this variant (Variation ID: 49246). For these reasons, this variant has been classified as Pathogenic.
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift 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: VCV000049246 / PMID: 12111193). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A novel de novo mutation in the TSC2 gene in a Chinese patient with tuberous sclerosis complex. | Li W | Journal of neurogenetics | 2016 | PMID: 27776463 |
| 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 |
| Somatic mosaicism is rare in unaffected parents of patients with sporadic tuberous sclerosis. | Roberts PS | Journal of medical genetics | 2004 | PMID: 15121797 |
| 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 |
| 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 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSC2 | - | - | - | - |
Text-mined citations for rs137854076 ...
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 Oct 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.