Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.5% (96/6614) Finnish chromosomes
ClinVar Genomic variation as it relates to human health
NM_000368.5(TSC1):c.2194C>T (p.His732Tyr)
Germline
Classification
Help
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.
(30)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(19); Likely benign(1)
Uncertain significance(1); Benign(19); Likely benign(1)
30
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000368.5(TSC1):c.2194C>T (p.His732Tyr)
Variation ID: 5103 Accession: VCV000005103.65
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.13 9: 132903665 (GRCh38) [ NCBI UCSC ] 9: 135779052 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 4, 2013 Oct 20, 2024 Aug 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000368.5:c.2194C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000359.1:p.His732Tyr missense NM_001162426.2:c.2191C>T NP_001155898.1:p.His731Tyr missense NM_001162427.2:c.2041C>T NP_001155899.1:p.His681Tyr missense NM_001362177.2:c.1831C>T NP_001349106.1:p.His611Tyr missense NC_000009.12:g.132903665G>A NC_000009.11:g.135779052G>A NG_012386.1:g.45969C>T LRG_486:g.45969C>T LRG_486t1:c.2194C>T LRG_486p1:p.His732Tyr Q92574:p.His732Tyr - Protein change
- H732Y, H611Y, H681Y, H731Y
- Other names
-
p.H732Y:CAT>TAT
- Canonical SPDI
- NC_000009.12:132903664:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00140 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00109
1000 Genomes Project 0.00140
Trans-Omics for Precision Medicine (TOPMed) 0.00213
The Genome Aggregation Database (gnomAD) 0.00343
The Genome Aggregation Database (gnomAD), exomes 0.00364
Exome Aggregation Consortium (ExAC) 0.00386
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| TSC1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4848 | 4906 | |
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
May 3, 2023 | RCV000005409.12 | |
| Benign (7) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000005410.35 | |
| Benign (8) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000034607.46 | |
| not provided (1) |
no classification provided
|
- | RCV000054851.12 | |
| Benign/Likely benign (9) |
criteria provided, multiple submitters, no conflicts
|
Apr 25, 2016 | RCV000118692.33 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 21, 2020 | RCV000129684.12 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jan 12, 2018 | RCV000278906.15 |
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
Help
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. |
|
|---|---|---|---|---|---|
|
Likely benign
(Mar 17, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
AllHighlyPenetrant
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000153107.1
First in ClinVar: May 17, 2014 Last updated: May 17, 2014 |
|
|
|
Benign
(May 03, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280942.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
|
|
|
Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000303858.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
|
Benign
(Apr 25, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000540593.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.5% (96/6614) Finnish chromosomes (less)
Method: Genome/Exome Filtration
|
|
|
Uncertain significance
(Sep 01, 2017)
|
criteria provided, single submitter
Method: research
|
Isolated focal cortical dysplasia type II
(Autosomal dominant inheritance)
Affected status: unknown, yes
Allele origin:
inherited,
unknown
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000598610.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
this variant was indentified in an individual with malformations of cortical development
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of neuronal migration (present)
Method: WES
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of neuronal migration (present)
Method: WES
|
|
|
Benign
(Oct 09, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000226570.5
First in ClinVar: Jun 29, 2015 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Benign
(Nov 21, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 1
Affected status: unknown
Allele origin:
unknown
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000883138.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
|
|
|
Benign
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 1
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002040060.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
|
|
|
Benign
(Oct 21, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002528856.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
|
Benign
(Sep 17, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 1
Affected status: unknown
Allele origin:
unknown
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000296907.3
First in ClinVar: Jul 31, 2016 Last updated: Dec 24, 2022 |
|
|
|
Benign
(Jul 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018700.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence … (more)
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. (less)
|
|
|
Benign
(Jun 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774053.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 06, 2024 |
|
|
|
Benign
(Sep 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001472363.4
First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024 |
|
|
|
Benign
(Jan 02, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000169091.10
First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
|
|
Benign
(Dec 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000844551.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
|
|
|
Benign
(Jan 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Isolated focal cortical dysplasia type II
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000478214.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
|
|
Benign
(Jan 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000478213.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
|
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000284695.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
|
|
|
Benign
(Sep 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 1
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004360817.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
|
Benign
(Nov 20, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184484.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Benign
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821976.14
First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024 |
Comment:
TSC1: BS1, BS2
Number of individuals with the variant: 38
|
|
|
probably not pathogenic
(Jul 13, 2012)
|
no assertion criteria provided
Method: research
|
not provided
Affected status: no
Allele origin:
germline
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043509.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Likely benign.
Number of individuals with the variant: 1
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808987.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740581.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953033.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001970901.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001921455.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000086410.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
|
|
|
not provided
(-)
|
no classification provided
Method: curation
|
TSC
Affected status: yes
Allele origin:
germline
|
Tuberous sclerosis database (TSC1)
Accession: SCV000065954.3
First in ClinVar: May 03, 2013 Last updated: Sep 16, 2013 |
|
|
|
Uncertain significance
(Jun 01, 2009)
|
Flagged submission
flagged submission
Method: literature only
Reason: Older claim that does not account for recent evidence
Source: ClinGen
|
RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025591.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
This variant, formerly titled FOCAL CORTICAL DYSPLASIA OF TAYLOR, TYPE IIB and TUBEROUS SCLEROSIS 1, has been reclassified based on the findings of Gumbinger et … (more)
This variant, formerly titled FOCAL CORTICAL DYSPLASIA OF TAYLOR, TYPE IIB and TUBEROUS SCLEROSIS 1, has been reclassified based on the findings of Gumbinger et al. (2009) and Rendtorff et al. (2005). Becker et al. (2002) showed that an amino acid change in residue 732 of hamartin from histidine to tyrosine (H732Y) was present in 14 of 40 (35%) cases of focal cortical dysplasia of the Taylor balloon cell type (see 607341) as compared with 2 of 200 (1%) controls. The change was produced by a C-to-T transition at nucleotide 2415 in exon 17 of the TSC1 gene. Exon 17 was the site of a number of other polymorphisms associated with focal cortical dysplasia, as were exons 14 and 22. The H732Y mutation had previously been observed at low frequencies in tuberous sclerosis (191100) and in unaffected individuals (Jones et al., 1997; van Slegtenhorst et al., 1999). Becker et al. (2002) interpreted the change and others as germline polymorphisms that predispose toward the cerebral lesion when combined with LOH in the other allele. The H732T substitution is located in a region of the hamartin protein involved in the interaction domain with tuberin, the product of the TSC2 gene (191092). In a detailed genotype-phenotype analysis of 33 patients with focal cortical dysplasia, including 23 with FCD type II, Gumbinger et al. (2009) identified several sequence variations in the TSC1 and TSC2 genes in both lesional brain tissue and blood of the patients, but in similar frequencies to that of the normal population. Most of the sequence alterations were silent. Gumbinger et al. (2009) concluded that focal cortical dysplasia is not caused by mutation in the TSC genes and does not appear to be promoted by TSC polymorphisms. Rendtorff et al. (2005) considered the H732Y mutation, which had been identified by Jones et al. (1997) in individuals without tuberous sclerosis, to be a polymorphism. (less)
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
this variant was indentified in an individual with malformations of cortical development
Comment:
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
TSC1: BS1, BS2
Comment:
Converted during submission to Likely benign.
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. |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.5% (96/6614) Finnish chromosomes
Comment:
this variant was indentified in an individual with malformations of cortical development
Comment:
This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
TSC1: BS1, BS2
Comment:
Converted during submission to Likely benign.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| RASGRF1-rearranged Cutaneous Melanocytic Neoplasms With Spitzoid Cytomorphology: A Clinicopathologic and Genetic Study of 3 Cases. | Goto K | The American journal of surgical pathology | 2022 | PMID: 34799483 |
| Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation. | McCreary D | JAMA network open | 2019 | PMID: 31664448 |
| Comprehensive genomic analysis of patients with disorders of cerebral cortical development. | Wiszniewski W | European journal of human genetics : EJHG | 2018 | PMID: 29706646 |
| Minute amounts of hamartin wildtype rescue the emergence of tuber-like lesions in conditional Tsc1 ablated mice. | Robens BK | Neurobiology of disease | 2016 | PMID: 27425891 |
| Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
| Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder. | Bahl S | Molecular autism | 2013 | PMID: 23514105 |
| Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
| Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. | Hoogeveen-Westerveld M | Human mutation | 2011 | PMID: 21309039 |
| Hamartin variants that are frequent in focal dysplasias and cortical tubers have reduced tuberin binding and aberrant subcellular distribution in vitro. | Lugnier C | Journal of neuropathology and experimental neurology | 2009 | PMID: 19918125 |
| Focal cortical dysplasia: a genotype-phenotype analysis of polymorphisms and mutations in the TSC genes. | Gumbinger C | Epilepsia | 2009 | PMID: 19175396 |
| Analysis of 65 tuberous sclerosis complex (TSC) patients by TSC2 DGGE, TSC1/TSC2 MLPA, and TSC1 long-range PCR sequencing, and report of 28 novel mutations. | Rendtorff ND | Human mutation | 2005 | PMID: 16114042 |
| Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis. | Becker AJ | Annals of neurology | 2002 | PMID: 12112044 |
| 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 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 |
| Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. | Jones AC | Human molecular genetics | 1997 | PMID: 9328481 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSC1 | - | - | - | - |
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Text-mined citations for rs118203657 ...
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the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
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Record last updated Nov 25, 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.