ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.5262C>G (p.Ile1754Met)
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.
Uncertain significance(1); Benign(5); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000548.5(TSC2):c.5262C>G (p.Ile1754Met)
Variation ID: 406068 Accession: VCV000406068.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2088448 (GRCh38) [ NCBI UCSC ] 16: 2138449 (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 Jan 1, 2018 Nov 24, 2024 Aug 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000548.5:c.5262C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Ile1754Met missense NM_000548.4:c.5262C>G NM_001077183.3:c.5061C>G NP_001070651.1:p.Ile1687Met missense NM_001114382.3:c.5193C>G NP_001107854.1:p.Ile1731Met missense NM_001318827.2:c.4953C>G NP_001305756.1:p.Ile1651Met missense NM_001318829.2:c.4917C>G NP_001305758.1:p.Ile1639Met missense NM_001318831.2:c.4530C>G NP_001305760.1:p.Ile1510Met missense NM_001318832.2:c.5094C>G NP_001305761.1:p.Ile1698Met missense NM_001363528.2:c.5064C>G NP_001350457.1:p.Ile1688Met missense NM_001370404.1:c.5130C>G NP_001357333.1:p.Ile1710Met missense NM_001370405.1:c.5121C>G NP_001357334.1:p.Ile1707Met missense NM_021055.3:c.5133C>G NP_066399.2:p.Ile1711Met missense NC_000016.10:g.2088448C>G NC_000016.9:g.2138449C>G NG_005895.1:g.44143C>G NG_008617.1:g.54773G>C LRG_487:g.44143C>G LRG_487t1:c.5262C>G - Protein change
- I1754M, I1510M, I1651M, I1687M, I1707M, I1710M, I1711M, I1698M, I1688M, I1639M, I1731M
- Other names
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- Canonical SPDI
- NC_000016.10:2088447:C:G
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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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0.00020 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00016
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
The Genome Aggregation Database (gnomAD) 0.00025
1000 Genomes Project 30x 0.00047
- 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 | ||
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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. |
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TSC2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10968 | 11169 |
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. |
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Benign (2) |
criteria provided, multiple submitters, no conflicts
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Nov 29, 2020 | RCV000572414.4 | |
Conflicting classifications of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 12, 2019 | RCV000589806.8 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Aug 26, 2024 | RCV001086420.11 | |
TSC2-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Jun 17, 2024 | RCV004735537.1 |
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. |
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Uncertain significance
(Jun 16, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697477.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The TSC2 c.5262C>G (p.Ile1754Met) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant. … (more)
Variant summary: The TSC2 c.5262C>G (p.Ile1754Met) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant. This variant was found in 6/119900 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000586 (6/10236). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic TSC2 variant (0.0000688), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance - possibly benign variant until additional information becomes available. (less)
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Benign
(Feb 12, 2019)
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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: SCV001935518.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Benign
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002040268.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
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Benign
(Nov 29, 2020)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002534043.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544479.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
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Benign
(Nov 02, 2020)
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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: SCV000664736.5
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)
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Likely benign
(Aug 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV005404626.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease … (more)
This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. (less)
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549120.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TSC2 p.Ile1651Met variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP … (more)
The TSC2 p.Ile1651Met variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs397515318) and in ClinVar (alias: NM_000548.4:c.5262C>G (p.Ile1754Met); classified as conflicting interpretations of pathogenicity with benign by Invitae and VUS by Ambry Genetics and Integrated Genetics; associated conditions are Tuberous sclerosis 2 and Hereditary cancer-predisposing syndrome) The variant was identified in control databases in 21 of 281550 chromosomes at a frequency of 0.000075 (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: African in 19 of 24858 chromosomes (freq: 0.000764), Latino in 1 of 35422 chromosomes (freq: 0.000028) and European (non-Finnish) in 1 of 128140 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other and South Asian populations. The p.Ile1651 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Ile1651Met variant occurs in the first three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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Uncertain significance
(Jun 17, 2024)
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no assertion criteria provided
Method: clinical testing
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TSC2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005348995.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The TSC2 c.5262C>G variant is predicted to result in the amino acid substitution p.Ile1754Met. To our knowledge, this variant has not been reported in the … (more)
The TSC2 c.5262C>G variant is predicted to result in the amino acid substitution p.Ile1754Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.076% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs397515318 ...
HelpRecord last updated Jan 19, 2025
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.