In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1500 of the TSC2 protein (p.Val1500Leu).
ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.4498G>C (p.Val1500Leu)
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.
(2)
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.
Uncertain significance
2
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000548.5(TSC2):c.4498G>C (p.Val1500Leu)
Variation ID: 2918467 Accession: VCV002918467.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2084955 (GRCh38) [ NCBI UCSC ] 16: 2134956 (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 Feb 20, 2024 Apr 20, 2024 Aug 16, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000548.5:c.4498G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Val1500Leu missense NM_001077183.3:c.4297G>C NP_001070651.1:p.Val1433Leu missense NM_001114382.3:c.4429G>C NP_001107854.1:p.Val1477Leu missense NM_001318827.2:c.4189G>C NP_001305756.1:p.Val1397Leu missense NM_001318829.2:c.4153G>C NP_001305758.1:p.Val1385Leu missense NM_001318831.2:c.3766G>C NP_001305760.1:p.Val1256Leu missense NM_001318832.2:c.4330G>C NP_001305761.1:p.Val1444Leu missense NM_001363528.2:c.4300G>C NP_001350457.1:p.Val1434Leu missense NM_001370404.1:c.4366G>C NP_001357333.1:p.Val1456Leu missense NM_001370405.1:c.4369G>C NP_001357334.1:p.Val1457Leu missense NM_001406663.1:c.4495G>C NP_001393592.1:p.Val1499Leu missense NM_001406664.1:c.4426G>C NP_001393593.1:p.Val1476Leu missense NM_001406665.1:c.4420G>C NP_001393594.1:p.Val1474Leu missense NM_001406667.1:c.4390G>C NP_001393596.1:p.Val1464Leu missense NM_001406668.1:c.4387G>C NP_001393597.1:p.Val1463Leu missense NM_001406670.1:c.4318G>C NP_001393599.1:p.Val1440Leu missense NM_001406671.1:c.4288G>C NP_001393600.1:p.Val1430Leu missense NM_001406673.1:c.4285G>C NP_001393602.1:p.Val1429Leu missense NM_001406675.1:c.4282G>C NP_001393604.1:p.Val1428Leu missense NM_001406676.1:c.4279G>C NP_001393605.1:p.Val1427Leu missense NM_001406677.1:c.4240G>C NP_001393606.1:p.Val1414Leu missense NM_001406678.1:c.4186G>C NP_001393607.1:p.Val1396Leu missense NM_001406679.1:c.4150G>C NP_001393608.1:p.Val1384Leu missense NM_001406680.1:c.3898G>C NP_001393609.1:p.Val1300Leu missense NM_001406681.1:c.3838G>C NP_001393610.1:p.Val1280Leu missense NM_001406682.1:c.3829G>C NP_001393611.1:p.Val1277Leu missense NM_001406683.1:c.3829G>C NP_001393612.1:p.Val1277Leu missense NM_001406684.1:c.3826G>C NP_001393613.1:p.Val1276Leu missense NM_001406685.1:c.3700G>C NP_001393614.1:p.Val1234Leu missense NM_001406686.1:c.3700G>C NP_001393615.1:p.Val1234Leu missense NM_001406687.1:c.3697G>C NP_001393616.1:p.Val1233Leu missense NM_001406688.1:c.3697G>C NP_001393617.1:p.Val1233Leu missense NM_001406689.1:c.3085G>C NP_001393618.1:p.Val1029Leu missense NM_001406690.1:c.3025G>C NP_001393619.1:p.Val1009Leu missense NM_001406691.1:c.3022G>C NP_001393620.1:p.Val1008Leu missense NM_001406692.1:c.2956G>C NP_001393621.1:p.Val986Leu missense NM_001406693.1:c.2956G>C NP_001393622.1:p.Val986Leu missense NM_001406694.1:c.2956G>C NP_001393623.1:p.Val986Leu missense NM_001406695.1:c.2953G>C NP_001393624.1:p.Val985Leu missense NM_001406696.1:c.2953G>C NP_001393625.1:p.Val985Leu missense NM_001406697.1:c.2953G>C NP_001393626.1:p.Val985Leu missense NM_001406698.1:c.2695G>C NP_001393627.1:p.Val899Leu missense NM_021055.3:c.4369G>C NP_066399.2:p.Val1457Leu missense NR_176225.1:n.4450G>C non-coding transcript variant NR_176226.1:n.4698G>C non-coding transcript variant NR_176227.1:n.4626G>C non-coding transcript variant NR_176228.1:n.4447G>C non-coding transcript variant NR_176229.1:n.4407G>C non-coding transcript variant NC_000016.10:g.2084955G>C NC_000016.9:g.2134956G>C NG_005895.1:g.40650G>C LRG_487:g.40650G>C LRG_487t1:c.4498G>C LRG_487p1:p.Val1500Leu - Protein change
- V1009L, V1256L, V1277L, V1384L, V1429L, V1430L, V1434L, V1456L, V1463L, V1500L, V1280L, V1396L, V1427L, V1428L, V1433L, V985L, V986L, V1008L, V1234L, V1276L, V1385L, V1414L, V1440L, V1457L, V899L, V1029L, V1233L, V1300L, V1397L, V1444L, V1464L, V1474L, V1476L, V1477L, V1499L
- Other names
- -
- Canonical SPDI
- NC_000016.10:2084954:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| TSC2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10745 | 10944 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 16, 2023 | RCV003627559.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 28, 2023 | RCV004005917.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Aug 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004553690.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1500 of the TSC2 protein (p.Val1500Leu). (less)
|
|
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Uncertain Significance
(Jun 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004828445.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Number of individuals with the variant: 1
|
Comment:
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:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1500 of the TSC2 protein (p.Val1500Leu).
Citations for germline classification of this variant
Help| There 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 this variant ...
HelpRecord last updated Sep 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.