This missense variant replaces histidine with aspartic acid at codon 763 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.2287C>G (p.His763Asp)
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
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NM_000548.5(TSC2):c.2287C>G (p.His763Asp)
Variation ID: 3070887 Accession: VCV003070887.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 2072915 (GRCh38) [ NCBI UCSC ] 16: 2122916 (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 Apr 20, 2024 Nov 24, 2024 Jun 28, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000548.5:c.2287C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.His763Asp missense NM_001077183.3:c.2287C>G NP_001070651.1:p.His763Asp missense NM_001114382.3:c.2287C>G NP_001107854.1:p.His763Asp missense NM_001318827.2:c.2176C>G NP_001305756.1:p.His726Asp missense NM_001318829.2:c.2140C>G NP_001305758.1:p.His714Asp missense NM_001318831.2:c.1687C>G NP_001305760.1:p.His563Asp missense NM_001318832.2:c.2320C>G NP_001305761.1:p.His774Asp missense NM_001363528.2:c.2287C>G NP_001350457.1:p.His763Asp missense NM_001370404.1:c.2287C>G NP_001357333.1:p.His763Asp missense NM_001370405.1:c.2287C>G NP_001357334.1:p.His763Asp missense NM_001406663.1:c.2287C>G NP_001393592.1:p.His763Asp missense NM_001406664.1:c.2287C>G NP_001393593.1:p.His763Asp missense NM_001406665.1:c.2287C>G NP_001393594.1:p.His763Asp missense NM_001406667.1:c.2377C>G NP_001393596.1:p.His793Asp missense NM_001406668.1:c.2377C>G NP_001393597.1:p.His793Asp missense NM_001406670.1:c.2176C>G NP_001393599.1:p.His726Asp missense NM_001406671.1:c.2275C>G NP_001393600.1:p.His759Asp missense NM_001406673.1:c.2275C>G NP_001393602.1:p.His759Asp missense NM_001406675.1:c.2140C>G NP_001393604.1:p.His714Asp missense NM_001406676.1:c.2140C>G NP_001393605.1:p.His714Asp missense NM_001406677.1:c.2230C>G NP_001393606.1:p.His744Asp missense NM_001406678.1:c.2176C>G NP_001393607.1:p.His726Asp missense NM_001406679.1:c.2140C>G NP_001393608.1:p.His714Asp missense NM_001406680.1:c.1687C>G NP_001393609.1:p.His563Asp missense NM_001406681.1:c.1825C>G NP_001393610.1:p.His609Asp missense NM_001406682.1:c.1687C>G NP_001393611.1:p.His563Asp missense NM_001406683.1:c.1687C>G NP_001393612.1:p.His563Asp missense NM_001406684.1:c.1687C>G NP_001393613.1:p.His563Asp missense NM_001406685.1:c.1687C>G NP_001393614.1:p.His563Asp missense NM_001406686.1:c.1687C>G NP_001393615.1:p.His563Asp missense NM_001406687.1:c.1687C>G NP_001393616.1:p.His563Asp missense NM_001406688.1:c.1687C>G NP_001393617.1:p.His563Asp missense NM_001406689.1:c.943C>G NP_001393618.1:p.His315Asp missense NM_001406690.1:c.943C>G NP_001393619.1:p.His315Asp missense NM_001406691.1:c.943C>G NP_001393620.1:p.His315Asp missense NM_001406692.1:c.943C>G NP_001393621.1:p.His315Asp missense NM_001406693.1:c.943C>G NP_001393622.1:p.His315Asp missense NM_001406694.1:c.943C>G NP_001393623.1:p.His315Asp missense NM_001406695.1:c.943C>G NP_001393624.1:p.His315Asp missense NM_001406696.1:c.943C>G NP_001393625.1:p.His315Asp missense NM_001406697.1:c.943C>G NP_001393626.1:p.His315Asp missense NM_001406698.1:c.685C>G NP_001393627.1:p.His229Asp missense NM_021055.3:c.2287C>G NP_066399.2:p.His763Asp missense NR_176225.1:n.2437C>G non-coding transcript variant NR_176226.1:n.2616C>G non-coding transcript variant NR_176227.1:n.2616C>G non-coding transcript variant NR_176228.1:n.2437C>G non-coding transcript variant NR_176229.1:n.2397C>G non-coding transcript variant NC_000016.10:g.2072915C>G NC_000016.9:g.2122916C>G NG_005895.1:g.28610C>G LRG_487:g.28610C>G LRG_487t1:c.2287C>G LRG_487p1:p.His763Asp - Protein change
- H229D, H315D, H563D, H609D, H714D, H726D, H744D, H759D, H763D, H774D, H793D
- Other names
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- Canonical SPDI
- NC_000016.10:2072914: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 |
10758 | 10957 | |
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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May 4, 2023 | RCV004014389.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
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Jun 28, 2024 | RCV004787093.1 |
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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|---|---|---|---|---|---|
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Uncertain Significance
(May 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004833677.1
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)
|
Comment:
This missense variant replaces histidine with aspartic acid at codon 763 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces histidine with aspartic acid at codon 763 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Jun 28, 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
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV005402360.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
The TSC2 c.2287C>G (p.His763Asp) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but … (more)
The TSC2 c.2287C>G (p.His763Asp) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with tuberous sclerosis complex. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
|
Comment:
Comment:
The TSC2 c.2287C>G (p.His763Asp) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with tuberous sclerosis complex. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
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 missense variant replaces histidine with aspartic acid at codon 763 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The TSC2 c.2287C>G (p.His763Asp) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with tuberous sclerosis complex. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
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 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.