ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.5116C>T (p.Arg1706Cys)
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.
Uncertain significance(3); Benign(5); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000548.5(TSC2):c.5116C>T (p.Arg1706Cys)
Variation ID: 49912 Accession: VCV000049912.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2088095 (GRCh38) [ NCBI UCSC ] 16: 2138096 (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 Oct 20, 2024 Aug 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000548.5:c.5116C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Arg1706Cys missense NM_000548.4:c.5116C>T NM_001077183.3:c.4915C>T NP_001070651.1:p.Arg1639Cys missense NM_001114382.3:c.5047C>T NP_001107854.1:p.Arg1683Cys missense NM_001318827.2:c.4807C>T NP_001305756.1:p.Arg1603Cys missense NM_001318829.2:c.4771C>T NP_001305758.1:p.Arg1591Cys missense NM_001318831.2:c.4384C>T NP_001305760.1:p.Arg1462Cys missense NM_001318832.2:c.4948C>T NP_001305761.1:p.Arg1650Cys missense NM_001363528.2:c.4918C>T NP_001350457.1:p.Arg1640Cys missense NM_001370404.1:c.4984C>T NP_001357333.1:p.Arg1662Cys missense NM_001370405.1:c.4987C>T NP_001357334.1:p.Arg1663Cys missense NM_021055.3:c.4987C>T NP_066399.2:p.Arg1663Cys missense NC_000016.10:g.2088095C>T NC_000016.9:g.2138096C>T NG_005895.1:g.43790C>T NG_008617.1:g.55126G>A LRG_487:g.43790C>T LRG_487t1:c.5116C>T - Protein change
- R1706C, R1662C, R1663C, R1639C, R1640C, R1683C, R1462C, R1591C, R1603C, R1650C
- Other names
- p.R1706C:CGC>TGC
- Canonical SPDI
- NC_000016.10:2088094: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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0.00080 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
Exome Aggregation Consortium (ExAC) 0.00027
The Genome Aggregation Database (gnomAD) 0.00029
Trans-Omics for Precision Medicine (TOPMed) 0.00029
The Genome Aggregation Database (gnomAD), exomes 0.00030
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
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
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. |
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Likely benign (2) |
criteria provided, single submitter
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Jan 13, 2018 | RCV000043179.15 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Jul 20, 2021 | RCV000189943.14 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Aug 1, 2024 | RCV000512881.31 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2020 | RCV000571102.12 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV001082733.17 | |
See cases
|
Uncertain significance (1) |
criteria provided, single submitter
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Mar 17, 2022 | RCV002222154.8 |
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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Benign
(Jun 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000243610.8
First in ClinVar: Aug 07, 2015 Last updated: Mar 08, 2017 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Likely benign
(Mar 17, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918329.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: TSC2 c.5116C>T (p.Arg1706Cys) results in a non-conservative amino acid change located in the Rap GTPase activating protein domain of the encoded protein sequence. … (more)
Variant summary: TSC2 c.5116C>T (p.Arg1706Cys) results in a non-conservative amino acid change located in the Rap GTPase activating protein domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. The variant, c.5116C>T, has been reported in the literature in individuals affected with Tuberous Sclerosis Complex (Jozwiak_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Tuberous Sclerosis Complex. A functional study, Hoogeveen-Westerveld_2012, found the variant to act comparable to wild type protein and classified as probably neutral. An internal specimen reports the variant to co-occur with pathogenic FLCN, c.927_954dup28. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000395675.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Benign
(Oct 19, 2020)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002534016.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Jun 09, 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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Revvity Omics, Revvity
Accession: SCV004236975.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely benign
(Aug 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000608741.31
First in ClinVar: Oct 30, 2017 Last updated: Oct 20, 2024 |
Comment:
TSC2: BS1
Number of individuals with the variant: 5
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Benign
(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: SCV002040251.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
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Uncertain significance
(Mar 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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see cases
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002499719.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
ACMG categories: BP1
Number of individuals with the variant: 1
Clinical Features:
Seizure (present) , Arachnoid cyst (present)
Age: 0-9 years
Sex: male
Tissue: blood
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Benign
(Jul 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774082.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011325.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Benign
(Feb 01, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000285440.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
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Likely benign
(Feb 11, 2019)
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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: SCV000675489.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Nov 29, 2022)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV003839174.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
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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: SCV000066979.3
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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New mutations in non-syndromic primary ovarian insufficiency patients identified via whole-exome sequencing. | Patiño LC | Human reproduction (Oxford, England) | 2017 | PMID: 28505269 |
Genetic profiles of cervical tumors by high-throughput sequencing for personalized medical care. | Muller E | Cancer medicine | 2015 | PMID: 26155992 |
Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer. | Esteban-Jurado C | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25058500 |
Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex. | Hoogeveen-Westerveld M | Human mutation | 2013 | PMID: 22903760 |
Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. | Hoogeveen-Westerveld M | Human mutation | 2011 | PMID: 21309039 |
Tuberin and hamartin expression is reduced in the majority of subependymal giant cell astrocytomas in tuberous sclerosis complex consistent with a two-hit model of pathogenesis. | Jóźwiak S | Journal of child neurology | 2004 | PMID: 15072102 |
Text-mined citations for rs45517391 ...
HelpRecord last updated Oct 27, 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.