ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.5321G>C (p.Ser1774Thr)
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
-
NM_000548.5(TSC2):c.5321G>C (p.Ser1774Thr)
Variation ID: 41745 Accession: VCV000041745.49
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.3 16: 2088507 (GRCh38) [ NCBI UCSC ] 16: 2138508 (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 Oct 8, 2024 May 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000548.5:c.5321G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Ser1774Thr missense NM_000548.4:c.5321G>C NM_001077183.3:c.5120G>C NP_001070651.1:p.Ser1707Thr missense NM_001114382.3:c.5252G>C NP_001107854.1:p.Ser1751Thr missense NM_001318827.2:c.5012G>C NP_001305756.1:p.Ser1671Thr missense NM_001318829.2:c.4976G>C NP_001305758.1:p.Ser1659Thr missense NM_001318831.2:c.4589G>C NP_001305760.1:p.Ser1530Thr missense NM_001318832.2:c.5153G>C NP_001305761.1:p.Ser1718Thr missense NM_001363528.2:c.5123G>C NP_001350457.1:p.Ser1708Thr missense NM_001370404.1:c.5189G>C NP_001357333.1:p.Ser1730Thr missense NM_001370405.1:c.5180G>C NP_001357334.1:p.Ser1727Thr missense NM_021055.3:c.5192G>C NP_066399.2:p.Ser1731Thr missense NC_000016.10:g.2088507G>C NC_000016.9:g.2138508G>C NG_005895.1:g.44202G>C NG_008617.1:g.54714C>G LRG_487:g.44202G>C LRG_487t1:c.5321G>C P49815:p.Ser1774Thr - Protein change
- S1774T, S1659T, S1671T, S1708T, S1718T, S1727T, S1530T, S1707T, S1730T, S1731T, S1751T
- Other names
- -
- Canonical SPDI
- NC_000016.10:2088506: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.
-
0.01058 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00948
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01000
Trans-Omics for Precision Medicine (TOPMed) 0.01034
1000 Genomes Project 0.01058
1000 Genomes Project 30x 0.01109
The Genome Aggregation Database (gnomAD), exomes 0.00242
Exome Aggregation Consortium (ExAC) 0.00300
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. |
|||
TSC2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10739 | 10936 |
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 (7) |
criteria provided, multiple submitters, no conflicts
|
May 1, 2024 | RCV000034662.33 | |
Benign (2) |
criteria provided, single submitter
|
Jan 13, 2018 | RCV000054870.15 | |
Benign (6) |
criteria provided, multiple submitters, no conflicts
|
Apr 2, 2015 | RCV000118714.30 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 10, 2020 | RCV000163420.11 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV001084407.17 | |
Likely benign (1) |
criteria provided, single submitter
|
Nov 4, 2021 | RCV002482951.8 |
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
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
(Apr 06, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000213963.8
First in ClinVar: Mar 24, 2015 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
(Apr 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000230569.5
First in ClinVar: Jun 28, 2015 Last updated: May 30, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
Benign
(Jan 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000395683.3
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
(Mar 03, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001837394.1
First in ClinVar: Sep 10, 2021 Last updated: Sep 10, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 24728327, 17304050, 22903760)
|
|
Benign
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002039950.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
|
|
Benign
(Sep 10, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002534052.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
Benign
(May 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004010434.11
First in ClinVar: Jul 16, 2023 Last updated: Oct 08, 2024 |
Comment:
TSC2: BP4, BS1, BS2
Number of individuals with the variant: 8
|
|
Likely Benign
(Aug 19, 2015)
|
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: SCV000280897.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Comment:
Converted during submission to Likely benign.
|
|
Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000305252.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
Benign
(Jun 16, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697478.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Comment:
Variant summary: The TSC2 c.5321G>C (p.Ser1774Thr) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant … (more)
Variant summary: The TSC2 c.5321G>C (p.Ser1774Thr) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 359/119808 control chromosomes (6 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.033497 (342/10210). This frequency is about 487 times the estimated maximal expected allele frequency of a pathogenic TSC2 variant (0.0000688), strong evidence that this is a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. (less)
|
|
Benign
(Jun 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001157617.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 26, 2021 |
|
|
Likely benign
(Nov 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease, adult type
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002800432.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Benign
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004016155.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000261874.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
|
|
Likely benign
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005217013.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
AllHighlyPenetrant
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000153129.2
First in ClinVar: May 17, 2014 Last updated: Jul 06, 2014 |
Comment:
Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated … (more)
Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. (less)
|
|
no known pathogenicity
(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: SCV000043545.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to 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: SCV001809195.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 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: SCV001966702.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000086465.1
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 (TSC2)
Accession: SCV000066988.3
First in ClinVar: May 03, 2013 Last updated: Sep 16, 2013 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSC2 | - | - | - | - |
Text-mined citations for rs9209 ...
HelpRecord last updated Oct 13, 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.