ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.3598C>T (p.Arg1200Trp)
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.3598C>T (p.Arg1200Trp)
Variation ID: 49770 Accession: VCV000049770.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2080365 (GRCh38) [ NCBI UCSC ] 16: 2130366 (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 12, 2024 Feb 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000548.5:c.3598C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Arg1200Trp missense NM_000548.4:c.3598C>T NM_001077183.3:c.3466C>T NP_001070651.1:p.Arg1156Trp missense NM_001114382.3:c.3598C>T NP_001107854.1:p.Arg1200Trp missense NM_001318827.2:c.3358C>T NP_001305756.1:p.Arg1120Trp missense NM_001318829.2:c.3322C>T NP_001305758.1:p.Arg1108Trp missense NM_001318831.2:c.2866C>T NP_001305760.1:p.Arg956Trp missense NM_001318832.2:c.3499C>T NP_001305761.1:p.Arg1167Trp missense NM_001363528.2:c.3469C>T NP_001350457.1:p.Arg1157Trp missense NM_001370404.1:c.3466C>T NP_001357333.1:p.Arg1156Trp missense NM_001370405.1:c.3469C>T NP_001357334.1:p.Arg1157Trp missense NM_021055.3:c.3469C>T NP_066399.2:p.Arg1157Trp missense NC_000016.10:g.2080365C>T NC_000016.9:g.2130366C>T NG_005895.1:g.36060C>T LRG_487:g.36060C>T LRG_487t1:c.3598C>T LRG_487p1:p.Arg1200Trp P49815:p.Arg1200Trp - Protein change
- R1200W, R1156W, R1167W, R956W, R1108W, R1120W, R1157W
- Other names
- p.R1200W:CGG>TGG
- Canonical SPDI
- NC_000016.10:2080364: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.
The Genome Aggregation Database (gnomAD) 0.00001
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 |
10622 | 10797 |
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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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Apr 14, 2023 | RCV000190021.35 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 25, 2022 | RCV000043035.14 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Feb 21, 2024 | RCV000190880.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 22, 2021 | RCV002453340.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2022 | RCV002490595.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 25, 2023 | RCV004537174.1 |
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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Pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782406.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(May 20, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000615900.2
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2021 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity. Found in multiple individuals with expected phenotype for this gene, including de … (more)
The frequency of this variant in the general population is consistent with pathogenicity. Found in multiple individuals with expected phenotype for this gene, including de novo cases. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. (less)
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768956.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tuberous sclerosis-2 (MIM#613254). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical symptoms can be variable and subtle among affected individuals within the same family (PMIDs: 21332470, 31018109). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (both v2 and v3 listed 1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many unrelated individuals with tuberous sclerosis complex, and is associated with the mild phenotype (mild skin lesions, remitting epilepsy, and absence of severe ID or major organ involvement) (PMIDs: 21332470, 30255984 and ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies using HEK cells showed the variant restricted the TSC1-TSC2-dependent inhibition of TORC1 activity (PMID: 21332470). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Feb 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lymphangiomyomatosis
Isolated focal cortical dysplasia type II Tuberous sclerosis 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002775128.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
Affected status: yes
Allele origin:
germline
|
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University
Accession: SCV001423570.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
Number of individuals with the variant: 3
Ethnicity/Population group: Japanese
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Pathogenic
(Apr 14, 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: SCV000243693.10
First in ClinVar: Aug 07, 2015 Last updated: Apr 23, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: destabilization of the TSC1-TSC2 complex and reduced inhibition of downstream targets (Hoogeveen-Westerveld et al., 2011; Wentink et al., … (more)
Published functional studies demonstrate a damaging effect: destabilization of the TSC1-TSC2 complex and reduced inhibition of downstream targets (Hoogeveen-Westerveld et al., 2011; Wentink et al., 2012); While some individuals with this variant are reported to meet clinical diagnostic criteria for definite TSC, others have been reported to have a milder clinical presentation characterized primarily by the presence of skin findings with or without epilepsy (Wentink et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17304050, 18792920, 28149746, 20301399, 29655203, 21309039, 15798777, 11112665, 8824881, 9463313, 28178598, 22867869, 27406250, 29056246, 29308833, 31005478, 32917966, 32005694, 21332470, 32211034) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047668.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.3598C>T (p.Arg1200Trp) in TSC2 gene has been reported in the literature to segregate with tuberous sclerosis complex and a wide range of … (more)
The missense variant c.3598C>T (p.Arg1200Trp) in TSC2 gene has been reported in the literature to segregate with tuberous sclerosis complex and a wide range of phenotypes including some milder cases in many families(Wentink M et.al.,2012). Experimental studies have shown that this missense change results in an unstable protein and disrupts the normal function of TSC2 as a regulator of cellular growth and proliferation(Hoogeveen-Westerveld M et.al.,2011). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg1200Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes and allele frequency of 0.003187% is reported in gnomAD. The amino acid Arg at position 1200 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties.The amino acid change p.Arg1200Trp in TSC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Polyminimyoclonus (present) , Myoclonus (present) , Poor head control (present) , Seizure (present) , Hypomelanotic macule (present) , Brisk reflexes (present) , EEG abnormality (present)
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Pathogenic
(May 20, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004221438.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000032 (1/31378 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been … (more)
The frequency of this variant in the general population, 0.000032 (1/31378 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with tuberous sclerosis, including de novo inheritance, and segregation with disease (PMIDs: 8824881 (1996), 9463313 (1998), 17304050 (2007), 18792920 (2008), 22867869 (2013), 25039834 (2014), 28149746 (2017), 32005694 (2020), and 32211034 (2020)). Functional studies found that this variant causes a deleterious effect to TSC2 protein function (PMIDs: 21309039 (2011) and 21332470 (2012)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jan 30, 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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Invitae
Accession: SCV000765896.8
First in ClinVar: Dec 06, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1200 of the TSC2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1200 of the TSC2 protein (p.Arg1200Trp). This variant is present in population databases (rs45438205, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of TSC2-related conditions (PMID: 8824881, 9463313, 18792920, 21332470, 22867869, 25039834, 28149746). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3616C>T (p.Arg1199Trp). ClinVar contains an entry for this variant (Variation ID: 49770). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21309039, 21332470). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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TSC2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004752640.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The TSC2 c.3598C>T variant is predicted to result in the amino acid substitution p.Arg1200Trp. This variant has been reported in a large number of individuals … (more)
The TSC2 c.3598C>T variant is predicted to result in the amino acid substitution p.Arg1200Trp. This variant has been reported in a large number of individuals and families with variable, often mild, manifestations of tuberous sclerosis complex (see for example, Wilson et al. 1996. PubMed ID: 8824881; Altarescu et al. 2008. PubMed ID: 18792920; Hoogeveen-Westerveld et al. 2011. PubMed ID: 21309039; Wentink et al. 2011. PubMed ID: 21332470; Butler et al. 2017. PubMed ID: 29056246). This variant is reported in 1 of ~31,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/16-2130366-C-T). It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/49770/). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848546.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg1200Trp variant in TSC2 (also described as p.Arg1199Trp in the literature) has been reported in >15 individuals with clinical features of tuberous sclerosis complex … (more)
The p.Arg1200Trp variant in TSC2 (also described as p.Arg1199Trp in the literature) has been reported in >15 individuals with clinical features of tuberous sclerosis complex (TSC), including at least 1 de novo occurrence and segregated with TSC in >7 affected family members from multiple families and with clinical features of TSC in other families, suggesting a milder phenotype in these families (Wilson 1996 PMID: 8824881, Au 1998 PMID: 9463313, Altarescu 2008 PMID: 18792920, Wentik 2012 PMID: 21332470, van Eeghen 2013 PMID: 22867869, Jansen 2014 PMID: 25039834, Pannu 2017 PMID: 28149746, Ding 2020 PMID: 32211034). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 49770) and had been identified in 0.006% (1/15418) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant may impact protein function (Wentik 2012 PMID: 21332470, Overwater 2016 PMID: 27406250) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant TSC. ACMG/AMP Criteria applied: PS4_Strong, PP1_Strong, PM6, PS3_Supporting, PP3. (less)
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Pathogenic
(Feb 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004930765.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21332470, 25039834, 32917966, 9463313, 32461669]. … (more)
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21332470, 25039834, 32917966, 9463313, 32461669]. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 27406250, 21332470]. (less)
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Pathogenic
(Nov 20, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000337423.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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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: SCV002040977.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
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Pathogenic
(May 25, 2022)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002548086.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: TSC2 c.3598C>T (p.Arg1200Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: TSC2 c.3598C>T (p.Arg1200Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247756 control chromosomes. c.3598C>T has been reported in the literature in multiple individuals affected with Tuberous Sclerosis Complex, including de novo inheritance, and in families where the variant was shown to segregate with disease (eg. Wilson_1996, Milunsky_2009, Wentink_2011, etc). Functional studies have shown the variant to inactivate the TSC1TSC2 complex, without preventing TSC1TSC2 binding (Wentink_2011). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003800556.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The TSC2 c.3598C>T; p.Arg1200Trp variant (rs45438205) is reported in the literature in individuals and families affected with tuberous sclerosis (Altarescu 2008, Au 1998, van Eeghen … (more)
The TSC2 c.3598C>T; p.Arg1200Trp variant (rs45438205) is reported in the literature in individuals and families affected with tuberous sclerosis (Altarescu 2008, Au 1998, van Eeghen 2013, Wentink 2012, Wilson 1996). This variant is also reported in ClinVar (Variation ID: 49770), but is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 1200 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.892). Additionally, functional assays demonstrate reduced complex formation and downstream signaling (Hoogeveen-Westerveld 2011, Wentink 2012). Based on available information, this variant is considered to be pathogenic. References: Altarescu et al. PGD on a recombinant allele: crossover between the TSC2 gene and 'linked' markers impairs accurate diagnosis. Prenat Diagn. 2008 Oct;28(10):929-33. Au et al. Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients. Am J Hum Genet. 1998 Feb;62(2):286-94. Hoogeveen-Westerveld et al. Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. Hum Mutat. 2011 Apr;32(4):424-35. van Eeghen et al. Central TSC2 missense mutations are associated with a reduced risk of infantile spasms. Epilepsy Res. 2013 Jan;103(1):83-7. Wentink et al. Functional characterization of the TSC2 c.3598C>T (p.R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds. Clin Genet. 2012 May;81(5):453-61. Wilson et al. Novel mutations detected in the TSC2 gene from both sporadic and familial TSC patients. Hum Mol Genet. 1996 Feb;5(2):249-56. (less)
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Pathogenic
(Apr 22, 2021)
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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: SCV002614912.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R1200W pathogenic mutation (also known as c.3598C>T), located in coding exon 29 of the TSC2 gene, results from a C to T substitution at … (more)
The p.R1200W pathogenic mutation (also known as c.3598C>T), located in coding exon 29 of the TSC2 gene, results from a C to T substitution at nucleotide position 3598. The arginine at codon 1200 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been identified in numerous individuals with clinical features associated with tuberous sclerosis (Wilson PJ et al. Hum Mol Genet, 1996 Feb;5:249-56; Au KS et al. Genet Med, 2007; Feb;9:88-100 Yu T et al. Clin Neurol Neurosurg, 2017 Mar;154:104-108; Ambry internal data); however some carriers and families have been show to present with milder phenotype than classic TSC1/2 pathogenic mutations (Wentink M et al. Clin Genet, 2012 May;81:453-61; Jansen AC. Dev Med Child Neurol, 2014 Dec;56:1134-1135; van Eeghen AM et al. Epilepsy Res, 2013 Jan;103:83-7; Pannu et al. Respir Med Case Rep 2017 Jan;20:113-115). This variant was demonstrated to disrupt the function TSC1-TSC2 complex in in vitro functional studies (Hoogeveen-Westerveld M et al. Hum Mutat, 2011 Apr;32:424-35; Wentink M et al. Clin Genet, 2012 May;81:453-61) This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation associated with reduced penetrance compared to other TSC2 mutations. (less)
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Pathogenic
(Nov 01, 2021)
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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: SCV001247496.21
First in ClinVar: May 09, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 2
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not provided
(-)
|
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: SCV000066834.3
First in ClinVar: May 04, 2013 Last updated: Sep 16, 2013 |
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not provided
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no classification provided
Method: literature only
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Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000245753.2
First in ClinVar: Sep 17, 2015 Last updated: Nov 05, 2022 |
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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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Mutation landscape of TSC1/TSC2 in Chinese patients with tuberous sclerosis complex. | Meng Y | Journal of human genetics | 2021 | PMID: 32917966 |
Tuberous Sclerosis Complex. | Adam MP | - | 2021 | PMID: 20301399 |
TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study. | Ogórek B | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32461669 |
Genotype and Phenotype Analysis of Chinese Children With Tuberous Sclerosis Complex: A Pediatric Cohort Study. | Ding Y | Frontiers in genetics | 2020 | PMID: 32211034 |
Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort. | Dong X | Journal of medical genetics | 2020 | PMID: 32005694 |
Genetic Etiologies, Diagnosis, and Treatment of Tuberous Sclerosis Complex. | Salussolia CL | Annual review of genomics and human genetics | 2019 | PMID: 31018109 |
Tuberous Sclerosis Complex Genotypes and Developmental Phenotype. | Farach LS | Pediatric neurology | 2019 | PMID: 31005478 |
Genetic Underpinnings of Renal Cell Carcinoma With Leiomyomatous Stroma. | Parilla M | The American journal of surgical pathology | 2019 | PMID: 30986793 |
Genetics, genomics, and genotype-phenotype correlations of TSC: Insights for clinical practice. | Peron A | American journal of medical genetics. Part C, Seminars in medical genetics | 2018 | PMID: 30255984 |
Severe bleeding complications and multiple kidney transplants in a patient with tuberous sclerosis complex caused by a novel TSC2 missense variant. | Živčić-Ćosić S | Croatian medical journal | 2017 | PMID: 29308833 |
Novel TSC1 and TSC2 gene mutations in Chinese patients with tuberous sclerosis complex. | Yu T | Clinical neurology and neurosurgery | 2017 | PMID: 28178598 |
Multifocal micronodular pneumocyte hyperplasia (MMPH) in a patient with tuberous sclerosis-evidence for long term stability. | Pannu BS | Respiratory medicine case reports | 2017 | PMID: 28149746 |
Genotype and brain pathology phenotype in children with tuberous sclerosis complex. | Overwater IE | European journal of human genetics : EJHG | 2016 | PMID: 27406250 |
Careful clinical observation continues to improve understanding of the phenotype in individuals with tuberous sclerosis complex. | Jansen AC | Developmental medicine and child neurology | 2014 | PMID: 25039834 |
Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex. | Hoogeveen-Westerveld M | Human mutation | 2013 | PMID: 22903760 |
Central TSC2 missense mutations are associated with a reduced risk of infantile spasms. | van Eeghen AM | Epilepsy research | 2013 | PMID: 22867869 |
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 |
Prenatal molecular diagnosis of tuberous sclerosis complex. | Milunsky A | American journal of obstetrics and gynecology | 2009 | PMID: 19254590 |
PGD on a recombinant allele: crossover between the TSC2 gene and 'linked' markers impairs accurate diagnosis. | Altarescu G | Prenatal diagnosis | 2008 | PMID: 18792920 |
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 |
Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients. | Au KS | American journal of human genetics | 1998 | PMID: 9463313 |
Novel mutations detected in the TSC2 gene from both sporadic and familial TSC patients. | Wilson PJ | Human molecular genetics | 1996 | PMID: 8824881 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSC2 | - | - | - | - |
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Text-mined citations for rs45438205 ...
HelpRecord last updated May 19, 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.