chr9-132903785-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000368.5(TSC1):c.2074C>T(p.Arg692Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,688 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R692R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000368.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.2074C>T | p.Arg692Ter | stop_gained | 17/23 | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.2074C>T | p.Arg692Ter | stop_gained | 17/23 | 1 | NM_000368.5 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461688Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727128
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Tuberous sclerosis 1 Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 25, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2023 | This sequence change creates a premature translational stop signal (p.Arg692*) 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 (PMID: 9242607, 10227394, 16114042, 16981987, 20547222, 22707517, 24633152, 26231267). ClinVar contains an entry for this variant (Variation ID: 48885). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
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 | Myriad Genetics, Inc. | Jun 22, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
not provided Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 25, 2021 | Reported multiple times in association with tuberous sclerosis complex (TSC) (vanSlegtenhorst et al., 1997; Rendtorff et al; 2005; TSC1 LOVD); 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; Published functional studies demonstrate that R692X reduces TSC1 protein stability and TSC1-TSC2 complex formation (Hoogeveen-Westerveld et al., 2010); This variant is associated with the following publications: (PMID: 18830229, 32555378, 9242607, 20547222, 31447099, 25782670, 16981987, 10227394, 10533067, 10363127, 24633152, 25525159, 26231267, 16114042, 31855466, 32211034, 33528079, 33087929) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 05, 2014 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. - |
Tuberous sclerosis syndrome Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 20, 2018 | The p.Arg692X variant in TSC1 is a well-established pathogenic variant for tuber ous sclerosis complex (TSC; Tuberous sclerosis LOVD database: http://chromium.lo vd.nl/LOVD2/TSC). It was absent from large population studies. This nonsense var iant leads to a premature termination codon at position 692, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the T SC1 gene is an established disease mechanism in individuals with TSC. In summary , this variant meets criteria to be classified as pathogenic for TSC in an autos omal dominant manner based upon predicted impact to the protein, presence in mul tiple affected individuals and absence in the general population. ACMG/AMP Crite ria applied: PVS1, PS4, PM2. - |
not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 20, 2021 | The p.R692* pathogenic mutation (also known as c.2074C>T), located in coding exon 15 of the TSC1 gene, results from a C to T substitution at nucleotide position 2074. This changes the amino acid from an arginine to a stop codon within coding exon 15. This mutation has been identified in multiple individuals with tuberous sclerosis complex (TSC) (van Slegtenhorst M et al. Science.1997 Aug;277:805-8; Niida Y et al. Hum. Mutat. 1999;14:412-22; Hoogeveen-Westerveld M et al. Biochim. Biophys. Acta. 2010 Sep;1802:774-81; Hung CC et al. BMC Med. Genet. 2006 Sep;7:72; Peron A et al. Am. J. Med. Genet. A. 2016 Jun;170:1538-44). Of note, this alteration is also designated as 2295C>T (R692X) in published literature. 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. - |
Malignant tumor of urinary bladder Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at