This variant has not been reported in the literature in individuals affected with TSC2-related conditions. 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. ClinVar contains an entry for this variant (Variation ID: 1734981). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1266 of the TSC2 protein (p.Leu1266Val).
ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.3796C>G (p.Leu1266Val)
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.3796C>G (p.Leu1266Val)
Variation ID: 1734981 Accession: VCV001734981.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2081780 (GRCh38) [ NCBI UCSC ] 16: 2131781 (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 Nov 29, 2022 May 1, 2024 Mar 21, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000548.5:c.3796C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Leu1266Val missense NM_001077183.3:c.3664C>G NP_001070651.1:p.Leu1222Val missense NM_001114382.3:c.3796C>G NP_001107854.1:p.Leu1266Val missense NM_001318827.2:c.3556C>G NP_001305756.1:p.Leu1186Val missense NM_001318829.2:c.3520C>G NP_001305758.1:p.Leu1174Val missense NM_001318831.2:c.3064C>G NP_001305760.1:p.Leu1022Val missense NM_001318832.2:c.3697C>G NP_001305761.1:p.Leu1233Val missense NM_001363528.2:c.3667C>G NP_001350457.1:p.Leu1223Val missense NM_001370404.1:c.3664C>G NP_001357333.1:p.Leu1222Val missense NM_001370405.1:c.3667C>G NP_001357334.1:p.Leu1223Val missense NM_001406663.1:c.3793C>G NP_001393592.1:p.Leu1265Val missense NM_001406664.1:c.3793C>G NP_001393593.1:p.Leu1265Val missense NM_001406665.1:c.3664C>G NP_001393594.1:p.Leu1222Val missense NM_001406667.1:c.3757C>G NP_001393596.1:p.Leu1253Val missense NM_001406668.1:c.3754C>G NP_001393597.1:p.Leu1252Val missense NM_001406670.1:c.3685C>G NP_001393599.1:p.Leu1229Val missense NM_001406671.1:c.3655C>G NP_001393600.1:p.Leu1219Val missense NM_001406673.1:c.3652C>G NP_001393602.1:p.Leu1218Val missense NM_001406675.1:c.3649C>G NP_001393604.1:p.Leu1217Val missense NM_001406676.1:c.3646C>G NP_001393605.1:p.Leu1216Val missense NM_001406677.1:c.3607C>G NP_001393606.1:p.Leu1203Val missense NM_001406678.1:c.3553C>G NP_001393607.1:p.Leu1185Val missense NM_001406679.1:c.3517C>G NP_001393608.1:p.Leu1173Val missense NM_001406680.1:c.3196C>G NP_001393609.1:p.Leu1066Val missense NM_001406681.1:c.3205C>G NP_001393610.1:p.Leu1069Val missense NM_001406682.1:c.3196C>G NP_001393611.1:p.Leu1066Val missense NM_001406683.1:c.3196C>G NP_001393612.1:p.Leu1066Val missense NM_001406684.1:c.3193C>G NP_001393613.1:p.Leu1065Val missense NM_001406685.1:c.3067C>G NP_001393614.1:p.Leu1023Val missense NM_001406686.1:c.3067C>G NP_001393615.1:p.Leu1023Val missense NM_001406687.1:c.3064C>G NP_001393616.1:p.Leu1022Val missense NM_001406688.1:c.3064C>G NP_001393617.1:p.Leu1022Val missense NM_001406689.1:c.2452C>G NP_001393618.1:p.Leu818Val missense NM_001406690.1:c.2323C>G NP_001393619.1:p.Leu775Val missense NM_001406691.1:c.2320C>G NP_001393620.1:p.Leu774Val missense NM_001406692.1:c.2323C>G NP_001393621.1:p.Leu775Val missense NM_001406693.1:c.2323C>G NP_001393622.1:p.Leu775Val missense NM_001406694.1:c.2323C>G NP_001393623.1:p.Leu775Val missense NM_001406695.1:c.2320C>G NP_001393624.1:p.Leu774Val missense NM_001406696.1:c.2320C>G NP_001393625.1:p.Leu774Val missense NM_001406697.1:c.2320C>G NP_001393626.1:p.Leu774Val missense NM_001406698.1:c.2062C>G NP_001393627.1:p.Leu688Val missense NM_021055.3:c.3667C>G NP_066399.2:p.Leu1223Val missense NR_176225.1:n.3817C>G NR_176226.1:n.3996C>G NR_176227.1:n.3993C>G NR_176228.1:n.3814C>G NR_176229.1:n.3774C>G NC_000016.10:g.2081780C>G NC_000016.9:g.2131781C>G NG_005895.1:g.37475C>G LRG_487:g.37475C>G LRG_487t1:c.3796C>G LRG_487p1:p.Leu1266Val - Protein change
- L1023V, L1216V, L1219V, L1222V, L1233V, L1253V, L818V, L1022V, L1174V, L1223V, L1252V, L688V, L774V, L1065V, L1066V, L1185V, L1217V, L1218V, L1229V, L1265V, L1069V, L1173V, L1186V, L1203V, L1266V, L775V
- Other names
- -
- Canonical SPDI
- NC_000016.10:2081779: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| 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
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Feb 7, 2022 | RCV002353100.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 21, 2023 | RCV003626714.2 |
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. |
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|---|---|---|---|---|---|
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Uncertain significance
(Mar 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004445815.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
This variant has not been reported in the literature in individuals affected with TSC2-related conditions. In summary, the available evidence is currently insufficient to determine … (more)
This variant has not been reported in the literature in individuals affected with TSC2-related conditions. 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. ClinVar contains an entry for this variant (Variation ID: 1734981). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1266 of the TSC2 protein (p.Leu1266Val). (less)
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Uncertain significance
(Feb 07, 2022)
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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: SCV002620121.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.L1266V variant (also known as c.3796C>G), located in coding exon 30 of the TSC2 gene, results from a C to G substitution at nucleotide … (more)
The p.L1266V variant (also known as c.3796C>G), located in coding exon 30 of the TSC2 gene, results from a C to G substitution at nucleotide position 3796. The leucine at codon 1266 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
Comment:
Comment:
The p.L1266V variant (also known as c.3796C>G), located in coding exon 30 of the TSC2 gene, results from a C to G substitution at nucleotide position 3796. The leucine at codon 1266 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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:
This variant has not been reported in the literature in individuals affected with TSC2-related conditions. 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. ClinVar contains an entry for this variant (Variation ID: 1734981). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1266 of the TSC2 protein (p.Leu1266Val).
Comment:
The p.L1266V variant (also known as c.3796C>G), located in coding exon 30 of the TSC2 gene, results from a C to G substitution at nucleotide position 3796. The leucine at codon 1266 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 29, 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.