ClinVar Genomic variation as it relates to human health
NM_000368.5(TSC1):c.989dup (p.Ser331fs)
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.989dup (p.Ser331fs)
Variation ID: 49135 Accession: VCV000049135.24
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 9q34.13 9: 132911492-132911493 (GRCh38) [ NCBI UCSC ] 9: 135786879-135786880 (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 1, 2024 Aug 5, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000368.5:c.989dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000359.1:p.Ser331fs frameshift NM_000368.4:c.989dupT NM_001162426.2:c.989dup NP_001155898.1:p.Ser331fs frameshift NM_001162427.2:c.836dup NP_001155899.1:p.Ser280fs frameshift NM_001362177.2:c.626dup NP_001349106.1:p.Ser210fs frameshift NC_000009.12:g.132911493dup NC_000009.11:g.135786880dup NG_012386.1:g.38141dup LRG_486:g.38141dup - Protein change
- S210fs, S331fs, S280fs
- Other names
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- Canonical SPDI
- NC_000009.12:132911492:A:AA
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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
Help
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
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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TSC1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4739 | 4788 |
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
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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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- | RCV000042390.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2022 | RCV000189866.10 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Aug 5, 2023 | RCV000201139.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 21, 2015 | RCV000414909.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 17, 2019 | RCV000491374.3 |
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
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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
(Jul 09, 2014)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000255870.2
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015 |
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Pathogenic
(Oct 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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Cortical dysplasia
Renal cortical cysts Renal insufficiency
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492767.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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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: SCV000782383.1
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015 |
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Pathogenic
(Aug 22, 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: SCV000243519.8
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported previously multiple times (sometimes using alternative nomenclature 1210insT) in association with TSC (van Slegtenhorst et al., 1999; Zhang et al., 1999; TSC1 LOVD).; Frameshift … (more)
Reported previously multiple times (sometimes using alternative nomenclature 1210insT) in association with TSC (van Slegtenhorst et al., 1999; Zhang et al., 1999; TSC1 LOVD).; Frameshift 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: 15798777, 31855466, 29655203, 25782670, 10570911, 23341583, 28968464, 10227394) (less)
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Pathogenic
(Aug 05, 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: SCV000931870.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49135). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49135). This variant is also known as c.990insT and c.1210insT. This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 10227394, 10570911, 23341583, 28968464). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser331Glufs*10) 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). (less)
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Pathogenic
(May 17, 2019)
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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: SCV000579945.6
First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024 |
Comment:
The c.989dupT pathogenic mutation, located in coding exon 8 of the TSC1 gene, results from a duplication of T at nucleotide position 989, causing a … (more)
The c.989dupT pathogenic mutation, located in coding exon 8 of the TSC1 gene, results from a duplication of T at nucleotide position 989, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in multiple individuals who met clinical criteria for tuberous sclerosis complex (TSC); this alteration is also referred to as 1210insT, 989insT, and c.990insT in the literature (van Slegtenhorst M et al. J Med Genet. 1999; 36(4):285-9; Zhang H et al. J Hum Genet. 1999; 44(6):391-6; Dunet V et al. BMJ Case Rep. 2013; 2013; Rosset C et al. PLoS ONE. 2017 Oct;12:e0185713). 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)
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Pathogenic
(Apr 15, 2019)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714331.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PVS1, PS4_moderate, PM2, PP4
Number of individuals with the variant: 1
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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: SCV002041075.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
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Pathogenic
(Dec 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV003806571.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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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: SCV000066180.3
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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Molecular analysis of TSC1 and TSC2 genes and phenotypic correlations in Brazilian families with tuberous sclerosis. | Rosset C | PloS one | 2017 | PMID: 28968464 |
Multiple pulmonary artery aneurysms in tuberous sclerosis complex. | Dunet V | BMJ case reports | 2013 | PMID: 23341583 |
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 |
Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex. | Zhang H | Journal of human genetics | 1999 | PMID: 10570911 |
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 |
Text-mined citations for rs118203478 ...
HelpRecord last updated Jun 02, 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.