16-2080365-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000548.5(TSC2):c.3598C>T(p.Arg1200Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,611,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1200P) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
TSC2
NM_000548.5 missense
NM_000548.5 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 5.42
Genes affected
TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-2080366-G-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 16-2080365-C-T is Pathogenic according to our data. Variant chr16-2080365-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 49770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2080365-C-T is described in Lovd as [Pathogenic]. Variant chr16-2080365-C-T is described in Lovd as [Pathogenic]. Variant chr16-2080365-C-T is described in Lovd as [Benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TSC2 | NM_000548.5 | c.3598C>T | p.Arg1200Trp | missense_variant | 30/42 | ENST00000219476.9 | NP_000539.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TSC2 | ENST00000219476.9 | c.3598C>T | p.Arg1200Trp | missense_variant | 30/42 | 5 | NM_000548.5 | ENSP00000219476.3 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
1
AN:
152204
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459408Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 725998
GnomAD4 exome
AF:
AC:
3
AN:
1459408
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
725998
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74356
GnomAD4 genome
AF:
AC:
1
AN:
152204
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74356
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:21Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tuberous sclerosis 2 Pathogenic:7Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University | Jul 10, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | 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 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 21, 2024 | 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]. - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2023 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 20, 2014 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 21, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 20, 2014 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | TSC2: PP1:Strong, PM5, PM6, PS4:Moderate, PM2:Supporting, PP3, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 20, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 19, 2024 | PP1_strong, PP3, PP4, PM5, PM6, PS3, PS4 - |
Tuberous sclerosis syndrome Pathogenic:3Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 25, 2022 | 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. - |
| not provided, no classification provided | curation | Tuberous sclerosis database (TSC2) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 25, 2024 | This missense variant replaces arginine with tryptophan at codon 1200 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies with this variant have demonstrated that phosphorylation of S6 kinase was significantly increased compared to wild-type, indicating impairment of TSC1-TSC2 dependent inhibition of TORC1 activity (PMID: 21309039, 21332470). This variant has been reported in numerous individuals affected with tuberous sclerosis complex (TSC; PMID: 8824881, 9463313, 18792920, 21332470, 22867869, 25039834). This variant has also been observed to segregate with disease in multiple tuberous sclerosis families (PMID: 18792920, 21332470). This variant has been identified in 1/31378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 30, 2021 | 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. - |
Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PP3+PS3+PS4_Moderate+PP1_Strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 01, 2022 | - - |
TSC2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 25, 2023 | 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 29, 2024 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Pathogenic
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4
MutPred
Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);.;.;.;.;Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);.;.;.;.;.;
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at