Not found in the total gnomAD dataset, and the data is high quality. Located in potentially critical domain of the protein. Found in multiple individuals with expected phenotype for this gene. 3 de novo cases with parental identity not confirmed.
ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.4839CAT[1] (p.Ile1614del)
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.
(7)
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.
Pathogenic
7
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.4839CAT[1] (p.Ile1614del)
Variation ID: 49325 Accession: VCV000049325.14
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 16p13.3 16: 2086369-2086371 (GRCh38) [ NCBI UCSC ] 16: 2136370-2136372 (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 Sep 16, 2013 Feb 14, 2024 Feb 23, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000548.5:c.4839CAT[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Ile1614del inframe deletion NM_000548.5:c.4842_4844del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000548.3:c.4842_4844delCAT NM_001077183.3:c.4638CAT[1] NP_001070651.1:p.Ile1547del inframe deletion NM_001114382.3:c.4770CAT[1] NP_001107854.1:p.Ile1591del inframe deletion NM_001318827.2:c.4530CAT[1] NP_001305756.1:p.Ile1511del inframe deletion NM_001318829.2:c.4494CAT[1] NP_001305758.1:p.Ile1499del inframe deletion NM_001318831.2:c.4107CAT[1] NP_001305760.1:p.Ile1370del inframe deletion NM_001318832.2:c.4671CAT[1] NP_001305761.1:p.Ile1558del inframe deletion NM_001363528.2:c.4641CAT[1] NP_001350457.1:p.Ile1548del inframe deletion NM_001370404.1:c.4707CAT[1] NP_001357333.1:p.Ile1570del inframe deletion NM_001370405.1:c.4710CAT[1] NP_001357334.1:p.Ile1571del inframe deletion NM_021055.3:c.4710CAT[1] NP_066399.2:p.Ile1571del inframe deletion NC_000016.10:g.2086369CAT[1] NC_000016.9:g.2136370CAT[1] NG_005895.1:g.42064CAT[1] LRG_487:g.42064CAT[1] - Protein change
- I1614del, I1511del, I1570del, I1547del, I1591del, I1499del, I1571del, I1370del, I1548del, I1558del
- Other names
- -
- Canonical SPDI
- NC_000016.10:2086368:CATCAT:CAT
-
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.
- -
-
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 |
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. |
|---|---|---|---|---|
| not provided (1) |
no classification provided
|
- | RCV000042585.3 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 23, 2023 | RCV000201210.9 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 10, 2020 | RCV001283509.6 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000255905.3
First in ClinVar: Oct 19, 2015 Last updated: Jan 26, 2021 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality. Located in potentially critical domain of the protein. Found in multiple individuals … (more)
Not found in the total gnomAD dataset, and the data is high quality. Located in potentially critical domain of the protein. Found in multiple individuals with expected phenotype for this gene. 3 de novo cases with parental identity not confirmed. (less)
|
|
|
Pathogenic
(Jun 10, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001818339.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); In-frame … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 17304050, 22867869, 25782670, 22748302, 9463313) (less)
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841872.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region was predicted to change the length of the … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region was predicted to change the length of the protein and disrupt normal protein function. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 22748302, 9463313). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000049325 / PMID: 9463313). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Bradycardia (present) , Atrioventricular block (present) , Wolff-Parkinson-White pattern (present) , Cerebral calcification (present) , Neoplasm of the heart (present) , Neonatal hyperbilirubinemia (present) , … (more)
Bradycardia (present) , Atrioventricular block (present) , Wolff-Parkinson-White pattern (present) , Cerebral calcification (present) , Neoplasm of the heart (present) , Neonatal hyperbilirubinemia (present) , Hyperammonemia (present) (less)
|
|
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Pathogenic
(Sep 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001222548.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 49325). This variant is also known as del (4770-4772); dl Ile 1591. This variant has been … (more)
ClinVar contains an entry for this variant (Variation ID: 49325). This variant is also known as del (4770-4772); dl Ile 1591. This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 9463313, 22748302; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.4842_4844del, results in the deletion of 1 amino acid(s) of the TSC2 protein (p.Ile1614del), but otherwise preserves the integrity of the reading frame. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
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: SCV001963954.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744482.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: curation
|
TSC
Affected status: yes
Allele origin:
germline
|
Tuberous sclerosis database (TSC2)
Accession: SCV000066379.3
First in ClinVar: May 04, 2013 Last updated: Sep 16, 2013 |
|
Comment:
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 17304050, 22867869, 25782670, 22748302, 9463313)
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region was predicted to change the length of the protein and disrupt normal protein function. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 22748302, 9463313). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000049325 / PMID: 9463313). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
ClinVar contains an entry for this variant (Variation ID: 49325). This variant is also known as del (4770-4772); dl Ile 1591. This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 9463313, 22748302; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.4842_4844del, results in the deletion of 1 amino acid(s) of the TSC2 protein (p.Ile1614del), but otherwise preserves the integrity of the reading frame. For these reasons, this variant has been classified as Pathogenic.
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:
Not found in the total gnomAD dataset, and the data is high quality. Located in potentially critical domain of the protein. Found in multiple individuals with expected phenotype for this gene. 3 de novo cases with parental identity not confirmed.
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 17304050, 22867869, 25782670, 22748302, 9463313)
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region was predicted to change the length of the protein and disrupt normal protein function. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 22748302, 9463313). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000049325 / PMID: 9463313). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
ClinVar contains an entry for this variant (Variation ID: 49325). This variant is also known as del (4770-4772); dl Ile 1591. This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 9463313, 22748302; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.4842_4844del, results in the deletion of 1 amino acid(s) of the TSC2 protein (p.Ile1614del), but otherwise preserves the integrity of the reading frame. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Central TSC2 missense mutations are associated with a reduced risk of infantile spasms. | van Eeghen AM | Epilepsy research | 2013 | PMID: 22867869 |
| Uterine angiosarcoma associated with lymphangioleiomyomatosis in a patient with tuberous sclerosis complex: an autopsy case report with immunohistochemical and genetic analysis. | Hayashi T | Human pathology | 2012 | PMID: 22748302 |
| Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. | Au KS | Genetics in medicine : official journal of the American College of Medical Genetics | 2007 | PMID: 17304050 |
| Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients. | Au KS | American journal of human genetics | 1998 | PMID: 9463313 |
| Monoanion inhibition and 35Cl nuclear magnetic resonance studies of renal dipeptidase. | Ferren LG | Biochemistry | 1975 | PMID: 48 |
Text-mined citations for rs137854331 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.