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: 1.1% (95/8654) East Asian; ClinVar: 1B, 1 LB
ClinVar Genomic variation as it relates to human health
NM_000368.5(TSC1):c.1960C>G (p.Gln654Glu)
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.
(18)
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(12); Likely benign(3)
Uncertain significance(1); Benign(12); Likely benign(3)
18
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.1960C>G (p.Gln654Glu)
Variation ID: 41692 Accession: VCV000041692.40
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.13 9: 132905618 (GRCh38) [ NCBI UCSC ] 9: 135781005 (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 12, 2013 Nov 24, 2024 Sep 5, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000368.5:c.1960C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000359.1:p.Gln654Glu missense NM_001162426.2:c.1957C>G NP_001155898.1:p.Gln653Glu missense NM_001162427.2:c.1807C>G NP_001155899.1:p.Gln603Glu missense NM_001362177.2:c.1597C>G NP_001349106.1:p.Gln533Glu missense NC_000009.12:g.132905618G>C NC_000009.11:g.135781005G>C NG_012386.1:g.44016C>G LRG_486:g.44016C>G LRG_486t1:c.1960C>G LRG_486p1:p.Gln654Glu Q92574:p.Gln654Glu - Protein change
- Q654E, Q603E, Q653E, Q533E
- Other names
-
p.GLN654Glu
p.Q654E:CAG>GAG
- Canonical SPDI
- NC_000009.12:132905617:G:C
-
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.
-
0.00200 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00029
Trans-Omics for Precision Medicine (TOPMed) 0.00039
Exome Aggregation Consortium (ExAC) 0.00082
The Genome Aggregation Database (gnomAD), exomes 0.00085
1000 Genomes Project 0.00200
1000 Genomes Project 30x 0.00234
- 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 |
4850 | 4908 | |
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. |
|---|---|---|---|---|
| Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2022 | RCV000034604.22 | |
| Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 25, 2016 | RCV000186670.16 | |
| Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
|
Sep 5, 2024 | RCV000234486.19 | |
| not provided (1) |
no classification provided
|
- | RCV000054846.2 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 28, 2020 | RCV000570330.4 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000303855.1
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: SCV000540594.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 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: 1.1% (95/8654) East Asian; ClinVar: 1B, 1 LB (less)
Method: Genome/Exome Filtration
|
|
|
Benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001137934.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Benign
(Feb 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV001146266.1
First in ClinVar: Jan 18, 2020 Last updated: Jan 18, 2020 |
|
|
|
Benign
(Nov 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000169088.12
First in ClinVar: Jun 23, 2014 Last updated: Dec 06, 2016 |
Comment:
This variant is associated with the following publications: (PMID: 25498131, 22703879, 10570911, 26332594, 16981987, 16554133, 22490766, 29740858, 30794603, 32211034)
|
|
|
Benign
(Apr 28, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002530946.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
|
Benign
(Feb 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774052.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 06, 2024 |
|
|
|
Benign
(Nov 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 1
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004360820.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
|
Benign
(Aug 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000664738.5
First in ClinVar: Jan 01, 2018 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)
|
|
|
Likely benign
(Jul 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004156643.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
TSC1: BP4, BS1
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Mar 18, 2016)
|
criteria provided, single submitter
Method: reference population
|
Tuberous sclerosis 1
Affected status: unknown
Allele origin:
germline
|
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267545.1
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
Number of individuals with the variant: 3
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
|
|
|
Likely benign
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 1
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782391.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
|
|
|
Likely benign
(Aug 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000334326.4
First in ClinVar: Dec 06, 2016 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Benign
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 1
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002040077.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
|
|
|
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: SCV000284686.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
|
|
|
Benign
(Sep 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV005404627.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
This variant is considered benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed … (more)
This variant is considered benign. 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. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. (less)
|
|
|
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: SCV000043512.1 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)
|
|
|
not provided
(-)
|
no classification provided
Method: curation
|
TSC
Affected status: yes
Allele origin:
germline
|
Tuberous sclerosis database (TSC1)
Accession: SCV000065893.3
First in ClinVar: May 03, 2013 Last updated: Sep 16, 2013 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This variant is associated with the following publications: (PMID: 25498131, 22703879, 10570911, 26332594, 16981987, 16554133, 22490766, 29740858, 30794603, 32211034)
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: BP4, BS1
Comment:
This variant is considered benign. 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. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
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: 1.1% (95/8654) East Asian; ClinVar: 1B, 1 LB
Comment:
This variant is associated with the following publications: (PMID: 25498131, 22703879, 10570911, 26332594, 16981987, 16554133, 22490766, 29740858, 30794603, 32211034)
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: BP4, BS1
Comment:
This variant is considered benign. 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. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Comment:
Converted during submission to Likely benign.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutation landscape of TSC1/TSC2 in Chinese patients with tuberous sclerosis complex. | Meng Y | Journal of human genetics | 2021 | PMID: 32917966 |
| Genotype and Phenotype Analysis of Chinese Children With Tuberous Sclerosis Complex: A Pediatric Cohort Study. | Ding Y | Frontiers in genetics | 2020 | PMID: 32211034 |
| Germline mutation of TSC1 or TSC2 gene in Chinese patients with bilateral renal angiomyolipomas and mutation spectrum of Chinese TSC patients. | Jiangyi W | Aging | 2020 | PMID: 31927531 |
| Familial multifocal micronodular pneumocyte hyperplasia with a novel splicing mutation in TSC1: Three cases in one family. | Shoji T | PloS one | 2019 | PMID: 30794603 |
| Novel mutations in Chinese Han patients with tuberous sclerosis complex: Case series and review of the published work. | Zheng LY | The Journal of dermatology | 2018 | PMID: 29740858 |
| Prenatal diagnosis of tuberous sclerosis complex using fetal ultrasonography and magnetic resonance imaging and genetic testing. | Wang CC | Taiwanese journal of obstetrics & gynecology | 2018 | PMID: 29458892 |
| Actionable Genes, Core Databases, and Locus-Specific Databases. | Pinard A | Human mutation | 2016 | PMID: 27600092 |
| Identification of Medically Actionable Secondary Findings in the 1000 Genomes. | Olfson E | PloS one | 2015 | PMID: 26332594 |
| Quick genetic screening using targeted next-generation sequencing in patients with tuberous sclerosis. | Liu Q | Journal of child neurology | 2015 | PMID: 24789117 |
| Mutational analysis of paediatric patients with tuberous sclerosis complex in Korea: genotype and epilepsy. | Lee JS | Epileptic disorders : international epilepsy journal with videotape | 2014 | PMID: 25498131 |
| Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder. | Bahl S | Molecular autism | 2013 | PMID: 23514105 |
| Mutational analysis of TSC1 and TSC2 in Japanese patients with tuberous sclerosis complex revealed higher incidence of TSC1 patients than previously reported. | Niida Y | Journal of human genetics | 2013 | PMID: 23389244 |
| 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 |
| High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism. | Kelleher RJ 3rd | PloS one | 2012 | PMID: 22558107 |
| Identification of TSC1 and TSC2 mutations in Korean patients with tuberous sclerosis complex. | Jang MA | Pediatric neurology | 2012 | PMID: 22490766 |
| [Mutation screening and prenatal diagnosis of tuberous sclerosis complex]. | Li W | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2011 | PMID: 21811971 |
| Prenatal molecular diagnosis of tuberous sclerosis complex. | Milunsky A | American journal of obstetrics and gynecology | 2009 | PMID: 19254590 |
| Molecular and clinical analyses of 84 patients with tuberous sclerosis complex. | Hung CC | BMC medical genetics | 2006 | PMID: 16981987 |
| Mutational analysis of TSC1 and TSC2 in Korean patients with tuberous sclerosis complex. | Choi JE | Brain & development | 2006 | PMID: 16554133 |
| [Analysis of gene mutation in patients with tuberous sclerosis complex with polymerase chain reaction-single strand conformation polymorphism]. | Feng JH | Zhonghua er ke za zhi = Chinese journal of pediatrics | 2003 | PMID: 14756965 |
| Why are some human disease-associated mutations fixed in mice? | Gao L | Trends in genetics : TIG | 2003 | PMID: 14642745 |
| Novel TSC1 and TSC2 mutations in Japanese patients with tuberous sclerosis complex. | Yamamoto T | Brain & development | 2002 | PMID: 12015165 |
| Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex. | Zhang H | Journal of human genetics | 1999 | PMID: 10570911 |
| Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. | van Slegtenhorst M | Science (New York, N.Y.) | 1997 | PMID: 9242607 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSC1 | - | - | - | - |
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Text-mined citations for rs75820036 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 30, 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.