ClinVar Genomic variation as it relates to human health
NM_000368.5(TSC1):c.2356C>T (p.Arg786Ter)
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_000368.5(TSC1):c.2356C>T (p.Arg786Ter)
Variation ID: 48943 Accession: VCV000048943.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.13 9: 132902640 (GRCh38) [ NCBI UCSC ] 9: 135778027 (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 Apr 15, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000368.5:c.2356C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000359.1:p.Arg786Ter nonsense NM_001162426.2:c.2353C>T NP_001155898.1:p.Arg785Ter nonsense NM_001162427.2:c.2203C>T NP_001155899.1:p.Arg735Ter nonsense NM_001362177.2:c.1993C>T NP_001349106.1:p.Arg665Ter nonsense NC_000009.12:g.132902640G>A NC_000009.11:g.135778027G>A NG_012386.1:g.46994C>T LRG_486:g.46994C>T LRG_486t1:c.2356C>T LRG_486p1:p.Arg786Ter - Protein change
- R786*, R735*, R785*, R665*
- Other names
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- Canonical SPDI
- NC_000009.12:132902639:G:A
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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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TSC1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4666 | 4715 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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not provided (1) |
no classification provided
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- | RCV000042194.3 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Sep 27, 2023 | RCV000201048.15 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 18, 2016 | RCV000415379.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 5, 2021 | RCV000491852.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2024 | RCV000519452.8 |
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
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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)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 1
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782393.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
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Pathogenic
(Jun 10, 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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Athena Diagnostics Inc
Accession: SCV000255857.3
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2018 |
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Pathogenic
(Apr 05, 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: SCV000579943.5
First in ClinVar: Jun 25, 2017 Last updated: Nov 29, 2022 |
Comment:
The p.R786* pathogenic mutation (also known as c.2356C>T), located in coding exon 16 of the TSC1 gene, results from a C to T substitution at … (more)
The p.R786* pathogenic mutation (also known as c.2356C>T), located in coding exon 16 of the TSC1 gene, results from a C to T substitution at nucleotide position 2356. This changes the amino acid from an arginine to a stop codon within coding exon 16. This mutation has been detected in both sporadic and familial tuberous sclerosis complex (TSC) cases (van Slegtenhorst M et al. Science. 1997 Aug;277:805-8; Hung CC et al. BMC Med. Genet. 2006 Sep;7:72). 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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 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: SCV004701553.2
First in ClinVar: Mar 10, 2024 Last updated: Apr 15, 2024 |
Comment:
TSC1: PVS1, PM2, PS4:Moderate
Number of individuals with the variant: 1
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Pathogenic
(Dec 11, 2019)
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criteria provided, single submitter
Method: research
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Tuberous sclerosis 1
(Sporadic)
Affected status: yes
Allele origin:
de novo
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Cavalleri Lab, Royal College of Surgeons in Ireland
Accession: SCV001160789.1
First in ClinVar: Apr 15, 2020 Last updated: Apr 15, 2020 |
Comment:
ACMG evidence PVS1, PS2, PM2, PP5
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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 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002040775.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
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Pathogenic
(Aug 05, 2022)
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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: SCV000616904.3
First in ClinVar: Dec 19, 2017 Last updated: Jan 07, 2023 |
Comment:
Reported previously multiple times in association with tuberous sclerosis complex (van Slegtenhorst et al., 1997; Au et al., 2007; TSC1 LOVD); Nonsense variant predicted to … (more)
Reported previously multiple times in association with tuberous sclerosis complex (van Slegtenhorst et al., 1997; Au et al., 2007; 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; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11112665, 16981987, 9328481, 29476190, 32532290, 25525159, 9242607, 9924605, 10363127, 9803264, 9863590, 10227394, 10533067, 25498131, 15798777, 17304050, 30693677, 32211034, 32313033, 32238909, 31031587, 30787465, 34480426, 34849272, 31377847) (less)
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Pathogenic
(Sep 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000552281.10
First in ClinVar: Oct 19, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg786*) in the TSC1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg786*) 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: 9242607, 9803264, 9863590, 9924605, 10227394, 10363127, 10533067, 11112665, 16981987). This variant is also known as 2577C>T. ClinVar contains an entry for this variant (Variation ID: 48943). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 18, 2016)
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no assertion criteria provided
Method: clinical testing
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Cardiac rhabdomyoma
Hamartoma Seizure
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492663.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Pathogenic
(Jun 09, 2020)
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no assertion criteria provided
Method: clinical testing
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Tuberous sclerosis 1
Affected status: yes
Allele origin:
germline
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Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University
Accession: SCV001370505.1
First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020 |
Number of individuals with the variant: 2
Ethnicity/Population group: Japanese
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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 (TSC1)
Accession: SCV000065980.3
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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A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability. | Benson KA | European journal of human genetics : EJHG | 2020 | PMID: 32238909 |
Genotype and Phenotype Analysis of Chinese Children With Tuberous Sclerosis Complex: A Pediatric Cohort Study. | Ding Y | Frontiers in genetics | 2020 | PMID: 32211034 |
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 |
Molecular and clinical analyses of 84 patients with tuberous sclerosis complex. | Hung CC | BMC medical genetics | 2006 | PMID: 16981987 |
Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. | Dabora SL | American journal of human genetics | 2001 | PMID: 11112665 |
Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis. | Niida Y | Human mutation | 1999 | PMID: 10533067 |
Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation. | van Slegtenhorst M | Journal of medical genetics | 1999 | PMID: 10227394 |
Comprehensive mutation analysis of TSC1 using two-dimensional DNA electrophoresis with DGGE. | Dabora SL | Annals of human genetics | 1998 | PMID: 10363127 |
Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance. | Kwiatkowska J | Annals of human genetics | 1998 | PMID: 9924605 |
Mutations in the TSC1 gene account for a minority of patients with tuberous sclerosis. | Ali JB | Journal of medical genetics | 1998 | PMID: 9863590 |
A mutation screen of the TSC1 gene reveals 26 protein truncating mutations and 1 splice site mutation in a panel of 79 tuberous sclerosis patients. | Young JM | Annals of human genetics | 1998 | PMID: 9803264 |
Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. | van Slegtenhorst M | Science (New York, N.Y.) | 1997 | PMID: 9242607 |
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Text-mined citations for rs118203682 ...
HelpRecord last updated Apr 15, 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.