rs118203537
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000368.5(TSC1):c.1498C>T(p.Arg500*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TSC1
NM_000368.5 stop_gained
NM_000368.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.31
Genes affected
TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-132906080-G-A is Pathogenic according to our data. Variant chr9-132906080-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132906080-G-A is described in Lovd as [Pathogenic]. Variant chr9-132906080-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TSC1 | ENST00000298552.9 | c.1498C>T | p.Arg500* | stop_gained | 15/23 | 1 | NM_000368.5 | ENSP00000298552.3 | ||
| TSC1 | ENST00000490179.4 | c.1498C>T | p.Arg500* | stop_gained | 16/24 | 3 | ENSP00000495533.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461656Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727128
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
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1461656
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32
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0
AN XY:
727128
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
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32
EpiCase
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tuberous sclerosis 1 Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 18, 2023 | This sequence change creates a premature translational stop signal (p.Arg500*) in the TSC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 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: 10227394, 15798777, 31019026, 31564432, 32211034, 34573383). This variant is also known as 1719C>T R500X. ClinVar contains an entry for this variant (Variation ID: 48791). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University | Jun 09, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Stop-gained (nonsense): 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.It is not observed in the gnomAD v2.1.1 dataset. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000048791, PMID:10227394). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Dec 18, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PVS1+PM2_Supporting+PS4+PS2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 02, 2024 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10363127, 17304050, 18032745, 31019026, 32211034, 26540169, 15798777, 25525159, 10227394, 31564432, 34403804, 34573383, 32917966, 35918040, 28614114) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 03, 2021 | - - |
Lymphangiomyomatosis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PM4,PP3,PP4,PP5. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 30, 2020 | The p.R500* pathogenic mutation (also known as c.1498C>T), located in coding exon 13 of the TSC1 gene, results from a C to T substitution at nucleotide position 1498. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been reported in multiple individuals with tuberous sclerosis complex (TSC) (Dabora SL et al. Ann. Hum. Genet., 1998 Nov;62:491-504; van Slegtenhorst M et al. J. Med. Genet., 1999 Apr;36:285-9; Niida Y et al. Hum. Mutat., 1999;14:412-22; Sancak O et al. Eur. J. Hum. Genet., 2005 Jun;13:731-41; Au KS et al. Genet. Med., 2007 Feb;9:88-100; Tyburczy ME et al. PLoS Genet., 2015 Nov;11:e1005637; Tan NBL et al. J. Pediatr. Gastroenterol. Nutr., 2017 10;65:e96). 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. - |
Tuberous sclerosis syndrome Other:1
| not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
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