Functional studies indicate that P1675L is damaging to the protein (Hoogeveen-Westerveld et al., 2013; Aicher et al., 2001); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12205112, 28065512, 32211034, 22903760, 11290735, 9302281, 23504366, 15024740, 12136241, 11112665, 25782670, 15121797, 11829138, 22867869, 10205261, 12111193, 27406250, 29801666, 31505689, 32313033)
ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.5024C>T (p.Pro1675Leu)
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.
(17)
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.
Conflicting classifications of pathogenicity
Pathogenic(12); Uncertain significance(1)
Pathogenic(12); Uncertain significance(1)
17
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000548.5(TSC2):c.5024C>T (p.Pro1675Leu)
Variation ID: 12393 Accession: VCV000012393.30
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.3 16: 2087897 (GRCh38) [ NCBI UCSC ] 16: 2137898 (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 Oct 20, 2024 Apr 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000548.5:c.5024C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Pro1675Leu missense NM_000548.4:c.5024C>T NM_001077183.3:c.4823C>T NP_001070651.1:p.Pro1608Leu missense NM_001114382.3:c.4955C>T NP_001107854.1:p.Pro1652Leu missense NM_001318827.2:c.4715C>T NP_001305756.1:p.Pro1572Leu missense NM_001318829.2:c.4679C>T NP_001305758.1:p.Pro1560Leu missense NM_001318831.1:c.4292C>T NM_001318831.2:c.4292C>T NP_001305760.1:p.Pro1431Leu missense NM_001318832.2:c.4856C>T NP_001305761.1:p.Pro1619Leu missense NM_001363528.2:c.4826C>T NP_001350457.1:p.Pro1609Leu missense NM_001370404.1:c.4892C>T NP_001357333.1:p.Pro1631Leu missense NM_001370405.1:c.4895C>T NP_001357334.1:p.Pro1632Leu missense NM_021055.3:c.4895C>T NP_066399.2:p.Pro1632Leu missense NC_000016.10:g.2087897C>T NC_000016.9:g.2137898C>T NG_005895.1:g.43592C>T NG_008617.1:g.55324G>A LRG_487:g.43592C>T LRG_487t1:c.5024C>T P49815:p.Pro1675Leu - Protein change
- P1675L, P1631L, P1431L, P1572L, P1619L, P1632L, P1560L, P1608L, P1609L, P1652L
- Other names
- -
- Canonical SPDI
- NC_000016.10:2087896:C:T
-
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
|
Apr 4, 2024 | RCV000013201.42 | |
| not provided (1) |
no classification provided
|
- | RCV000043065.4 | |
| not provided (1) |
no classification provided
|
- | RCV000055436.4 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2023 | RCV000493720.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 8, 2023 | RCV002345240.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 28, 2021 | RCV002496339.3 | |
|
TSC2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
May 1, 2024 | RCV004734515.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000583057.4
First in ClinVar: Jul 02, 2017 Last updated: Apr 17, 2019 |
Comment:
Functional studies indicate that P1675L is damaging to the protein (Hoogeveen-Westerveld et al., 2013; Aicher et al., 2001); Not observed in large population cohorts (Lek … (more)
Functional studies indicate that P1675L is damaging to the protein (Hoogeveen-Westerveld et al., 2013; Aicher et al., 2001); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12205112, 28065512, 32211034, 22903760, 11290735, 9302281, 23504366, 15024740, 12136241, 11112665, 25782670, 15121797, 11829138, 22867869, 10205261, 12111193, 27406250, 29801666, 31505689, 32313033) (less)
|
|
|
Pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002041014.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
|
|
|
Pathogenic
(Jul 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: yes
Allele origin:
germline
|
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University
Accession: SCV002559806.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
Comment:
According to ACMG GL 2015, well-established in vitro functional studies supportive of a damaging effect of this variant (PS3), located in the GAP domain (PM1), … (more)
According to ACMG GL 2015, well-established in vitro functional studies supportive of a damaging effect of this variant (PS3), located in the GAP domain (PM1), absent from controls (PM2), assumed de novo (PM6). Multiple lines of computational evidence support a deleterious effect (PP3), and detected in the patient with clinically definitive tuberous sclerosis complex (PP4) and also reported as pathogenic in LOVD database (PP5). (less)
Number of individuals with the variant: 1
Ethnicity/Population group: Japanese
|
|
|
Pathogenic
(Mar 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556815.2
First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022 |
Comment:
The TSC2 c.5024C>T variant is classified as a PATHOGENIC variant (PS3, PS4, PP3, PP4, PP5) The variant is a single nucleotide change from a cytosine … (more)
The TSC2 c.5024C>T variant is classified as a PATHOGENIC variant (PS3, PS4, PP3, PP4, PP5) The variant is a single nucleotide change from a cytosine to a thymine at position 5024 which is predicted to change the proline at position 1675 in the protein to leucine. The variant is in exon 39 and is located in RAP GTPases activating protein domain of the TSC2 gene. Furthermore, functional studies have shown that this variant decreases TSC2 protein expression levels, disrupts TSC2 phosphorylation, and prevents proper TSC2 protein binding with TSC1 (PMID: 11290735, 22903760) (PS3). The variant is considered as a recurrent change in the TSC2 gene, and has been reported many times in individuals with Tuberous sclerosis in the heterozygous state (PMID:9302281). The variant is in dbSNP (rs45483392) but is absent from population databases (PS4). The variant has been reported in ClinVar (Variation ID: 12393) and HGMD (Accession #: CM971532) as pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The phenotype of this patient is highly specific for the TSC2 gene (PP4). (less)
|
|
|
Pathogenic
(Sep 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Lymphangiomyomatosis
Isolated focal cortical dysplasia type II Tuberous sclerosis 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002794088.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Mar 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002645527.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.P1675L pathogenic mutation (also known as c.5024C>T), located in coding exon 38 of the TSC2 gene, results from a C to T substitution at … (more)
The p.P1675L pathogenic mutation (also known as c.5024C>T), located in coding exon 38 of the TSC2 gene, results from a C to T substitution at nucleotide position 5024. The proline at codon 1675 is replaced by leucine, an amino acid with similar properties. This alteration has been found in multiple individuals who met diagnostic criteria for tuberous sclerosis complex (Ambry internal data; Feng JH et al. Hum. Mutat., 2004 Apr;23:397; Maheshwar MM et al. Hum. Mol. Genet.,1997 Oct;6:1991-6). In addition, in functional studies of the alteration, it was found that the TSC2 signal was significantly reduced compared to the wild-typed TSC1-TSC2 control (Hoogeveen-Westerveld M et al. Hum. Mutat., 2013 Jan;34:167-75). Lastly, further functional studies of this alteration demonstratedreduced phosphorylation and impaired interaction with hamartin (Aicher LD et al. J. Biol. Chem., 2001 Jun;276:21017-21). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004702734.8
First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024 |
Comment:
TSC2: PS2:Very Strong, PM2, PS4:Moderate, PP3, PS3:Supporting
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318630.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 9302281, 11520734, 12111193). Functional studies provide strong evidence of the variant having … (more)
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 9302281, 11520734, 12111193). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22903760, 11290735). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.965>=0.6, 3CNET: 0.939>=0.75). It is not observed in the gnomAD v2.1.1 dataset. A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000535873). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Generalized non-motor (absence) seizure (present) , Cortical tubers (present) , Cutaneous angiolipomas (present) , Adenoma sebaceum (present) , Hamartoma (present) , Intellectual disability (present) , … (more)
Generalized non-motor (absence) seizure (present) , Cortical tubers (present) , Cutaneous angiolipomas (present) , Adenoma sebaceum (present) , Hamartoma (present) , Intellectual disability (present) , Subependymal giant-cell astrocytoma (present) , Arachnoid cyst (present) (less)
|
|
|
Pathogenic
(Nov 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
de novo
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026007.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
|
|
|
Pathogenic
(Aug 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000844589.2
First in ClinVar: Jul 02, 2017 Last updated: Jan 26, 2024 |
Comment:
This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including both familial and de novo cases. This variant … (more)
This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including both familial and de novo cases. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11290735, 22903760) (less)
|
|
|
Pathogenic
(Mar 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003823702.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544425.7
First in ClinVar: Sep 04, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1675 of the TSC2 protein (p.Pro1675Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1675 of the TSC2 protein (p.Pro1675Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (TSC) (PMID: 9302281, 9463313, 10570911, 11112665, 11520734, 12111193, 15024740, 21520333, 22867869). In at least one individual the variant was observed to be de novo. This variant is also known as 5042C>T and P1657L. ClinVar contains an entry for this variant (Variation ID: 12393). 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 expected to disrupt TSC2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TSC2 function (PMID: 11290735, 22903760). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Uncertain significance
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809584.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
|
Pathogenic
(Oct 01, 1997)
|
no assertion criteria provided
Method: literature only
|
TUBEROUS SCLEROSIS 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033448.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 04, 2016 |
Comment on evidence:
In 4 unrelated patients with tuberous sclerosis-2 (613254), Maheshwar et al. (1997) identified a C-to-T transition at nucleotide 5042 of the TSC2 gene, which resulted … (more)
In 4 unrelated patients with tuberous sclerosis-2 (613254), Maheshwar et al. (1997) identified a C-to-T transition at nucleotide 5042 of the TSC2 gene, which resulted in a proline-to-leucine substitution at codon 1675 (P1675L). (less)
|
|
|
Pathogenic
(May 01, 2024)
|
no assertion criteria provided
Method: clinical testing
|
TSC2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005356881.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The TSC2 c.5024C>T variant is predicted to result in the amino acid substitution p.Pro1675Leu. This variant has been reported as causative for tuberous sclerosis, and … (more)
The TSC2 c.5024C>T variant is predicted to result in the amino acid substitution p.Pro1675Leu. This variant has been reported as causative for tuberous sclerosis, and was found to be de novo in at least one patient (Maheshwar et al. 1997. PubMed ID: 9302281; Dabora et al. 2001. PubMed ID: 11112665; Aicher et al. 2001. PubMed ID: 11290735; Hoogeveen-Westerveld et al. 2013. PubMed ID: 22903760). A functional study showed that this variant affected phosphorylation and reduced interaction with hamartin (Aicher et al. 2001. PubMed ID: 11290735). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: curation
|
LAM
Affected status: yes
Allele origin:
germline
|
Tuberous sclerosis database (TSC2)
Accession: SCV000083657.2
First in ClinVar: Sep 16, 2013 Last updated: Sep 16, 2013 |
|
|
|
not provided
(-)
|
no classification provided
Method: curation
|
TSC
Affected status: yes
Allele origin:
germline
|
Tuberous sclerosis database (TSC2)
Accession: SCV000066864.3
First in ClinVar: May 03, 2013 Last updated: Sep 16, 2013 |
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Comment:
Comment:
According to ACMG GL 2015, well-established in vitro functional studies supportive of a damaging effect of this variant (PS3), located in the GAP domain (PM1), absent from controls (PM2), assumed de novo (PM6). Multiple lines of computational evidence support a deleterious effect (PP3), and detected in the patient with clinically definitive tuberous sclerosis complex (PP4) and also reported as pathogenic in LOVD database (PP5).
Comment:
The TSC2 c.5024C>T variant is classified as a PATHOGENIC variant (PS3, PS4, PP3, PP4, PP5) The variant is a single nucleotide change from a cytosine to a thymine at position 5024 which is predicted to change the proline at position 1675 in the protein to leucine. The variant is in exon 39 and is located in RAP GTPases activating protein domain of the TSC2 gene. Furthermore, functional studies have shown that this variant decreases TSC2 protein expression levels, disrupts TSC2 phosphorylation, and prevents proper TSC2 protein binding with TSC1 (PMID: 11290735, 22903760) (PS3). The variant is considered as a recurrent change in the TSC2 gene, and has been reported many times in individuals with Tuberous sclerosis in the heterozygous state (PMID:9302281). The variant is in dbSNP (rs45483392) but is absent from population databases (PS4). The variant has been reported in ClinVar (Variation ID: 12393) and HGMD (Accession #: CM971532) as pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The phenotype of this patient is highly specific for the TSC2 gene (PP4).
Comment:
The p.P1675L pathogenic mutation (also known as c.5024C>T), located in coding exon 38 of the TSC2 gene, results from a C to T substitution at nucleotide position 5024. The proline at codon 1675 is replaced by leucine, an amino acid with similar properties. This alteration has been found in multiple individuals who met diagnostic criteria for tuberous sclerosis complex (Ambry internal data; Feng JH et al. Hum. Mutat., 2004 Apr;23:397; Maheshwar MM et al. Hum. Mol. Genet.,1997 Oct;6:1991-6). In addition, in functional studies of the alteration, it was found that the TSC2 signal was significantly reduced compared to the wild-typed TSC1-TSC2 control (Hoogeveen-Westerveld M et al. Hum. Mutat., 2013 Jan;34:167-75). Lastly, further functional studies of this alteration demonstratedreduced phosphorylation and impaired interaction with hamartin (Aicher LD et al. J. Biol. Chem., 2001 Jun;276:21017-21). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
TSC2: PS2:Very Strong, PM2, PS4:Moderate, PP3, PS3:Supporting
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 9302281, 11520734, 12111193). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22903760, 11290735). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.965>=0.6, 3CNET: 0.939>=0.75). It is not observed in the gnomAD v2.1.1 dataset. A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000535873). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including both familial and de novo cases. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11290735, 22903760)
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1675 of the TSC2 protein (p.Pro1675Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (TSC) (PMID: 9302281, 9463313, 10570911, 11112665, 11520734, 12111193, 15024740, 21520333, 22867869). In at least one individual the variant was observed to be de novo. This variant is also known as 5042C>T and P1657L. ClinVar contains an entry for this variant (Variation ID: 12393). 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 expected to disrupt TSC2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TSC2 function (PMID: 11290735, 22903760). For these reasons, this variant has been classified as Pathogenic.
Comment:
The TSC2 c.5024C>T variant is predicted to result in the amino acid substitution p.Pro1675Leu. This variant has been reported as causative for tuberous sclerosis, and was found to be de novo in at least one patient (Maheshwar et al. 1997. PubMed ID: 9302281; Dabora et al. 2001. PubMed ID: 11112665; Aicher et al. 2001. PubMed ID: 11290735; Hoogeveen-Westerveld et al. 2013. PubMed ID: 22903760). A functional study showed that this variant affected phosphorylation and reduced interaction with hamartin (Aicher et al. 2001. PubMed ID: 11290735). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted 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:
Functional studies indicate that P1675L is damaging to the protein (Hoogeveen-Westerveld et al., 2013; Aicher et al., 2001); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12205112, 28065512, 32211034, 22903760, 11290735, 9302281, 23504366, 15024740, 12136241, 11112665, 25782670, 15121797, 11829138, 22867869, 10205261, 12111193, 27406250, 29801666, 31505689, 32313033)
Comment:
According to ACMG GL 2015, well-established in vitro functional studies supportive of a damaging effect of this variant (PS3), located in the GAP domain (PM1), absent from controls (PM2), assumed de novo (PM6). Multiple lines of computational evidence support a deleterious effect (PP3), and detected in the patient with clinically definitive tuberous sclerosis complex (PP4) and also reported as pathogenic in LOVD database (PP5).
Comment:
The TSC2 c.5024C>T variant is classified as a PATHOGENIC variant (PS3, PS4, PP3, PP4, PP5) The variant is a single nucleotide change from a cytosine to a thymine at position 5024 which is predicted to change the proline at position 1675 in the protein to leucine. The variant is in exon 39 and is located in RAP GTPases activating protein domain of the TSC2 gene. Furthermore, functional studies have shown that this variant decreases TSC2 protein expression levels, disrupts TSC2 phosphorylation, and prevents proper TSC2 protein binding with TSC1 (PMID: 11290735, 22903760) (PS3). The variant is considered as a recurrent change in the TSC2 gene, and has been reported many times in individuals with Tuberous sclerosis in the heterozygous state (PMID:9302281). The variant is in dbSNP (rs45483392) but is absent from population databases (PS4). The variant has been reported in ClinVar (Variation ID: 12393) and HGMD (Accession #: CM971532) as pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The phenotype of this patient is highly specific for the TSC2 gene (PP4).
Comment:
The p.P1675L pathogenic mutation (also known as c.5024C>T), located in coding exon 38 of the TSC2 gene, results from a C to T substitution at nucleotide position 5024. The proline at codon 1675 is replaced by leucine, an amino acid with similar properties. This alteration has been found in multiple individuals who met diagnostic criteria for tuberous sclerosis complex (Ambry internal data; Feng JH et al. Hum. Mutat., 2004 Apr;23:397; Maheshwar MM et al. Hum. Mol. Genet.,1997 Oct;6:1991-6). In addition, in functional studies of the alteration, it was found that the TSC2 signal was significantly reduced compared to the wild-typed TSC1-TSC2 control (Hoogeveen-Westerveld M et al. Hum. Mutat., 2013 Jan;34:167-75). Lastly, further functional studies of this alteration demonstratedreduced phosphorylation and impaired interaction with hamartin (Aicher LD et al. J. Biol. Chem., 2001 Jun;276:21017-21). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
TSC2: PS2:Very Strong, PM2, PS4:Moderate, PP3, PS3:Supporting
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 9302281, 11520734, 12111193). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22903760, 11290735). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.965>=0.6, 3CNET: 0.939>=0.75). It is not observed in the gnomAD v2.1.1 dataset. A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000535873). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including both familial and de novo cases. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11290735, 22903760)
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1675 of the TSC2 protein (p.Pro1675Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (TSC) (PMID: 9302281, 9463313, 10570911, 11112665, 11520734, 12111193, 15024740, 21520333, 22867869). In at least one individual the variant was observed to be de novo. This variant is also known as 5042C>T and P1657L. ClinVar contains an entry for this variant (Variation ID: 12393). 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 expected to disrupt TSC2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TSC2 function (PMID: 11290735, 22903760). For these reasons, this variant has been classified as Pathogenic.
Comment:
The TSC2 c.5024C>T variant is predicted to result in the amino acid substitution p.Pro1675Leu. This variant has been reported as causative for tuberous sclerosis, and was found to be de novo in at least one patient (Maheshwar et al. 1997. PubMed ID: 9302281; Dabora et al. 2001. PubMed ID: 11112665; Aicher et al. 2001. PubMed ID: 11290735; Hoogeveen-Westerveld et al. 2013. PubMed ID: 22903760). A functional study showed that this variant affected phosphorylation and reduced interaction with hamartin (Aicher et al. 2001. PubMed ID: 11290735). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| De novo mutation of the TSC2 gene in patient with Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders (TAND) Phenotype: a case report. | Triono A | Annals of medicine and surgery (2012) | 2023 | PMID: 37228977 |
| First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants. | Reyna-Fabián ME | Scientific reports | 2020 | PMID: 32313033 |
| Assessment of Tuberous Sclerosis Complex Associated With Renal Lesions by Targeted Next-generation Sequencing in Mainland China. | Cai Y | Urology | 2017 | PMID: 28065512 |
| Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex. | Hoogeveen-Westerveld M | Human mutation | 2013 | PMID: 22903760 |
| Central TSC2 missense mutations are associated with a reduced risk of infantile spasms. | van Eeghen AM | Epilepsy research | 2013 | PMID: 22867869 |
| LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
| 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 |
| Novel TSC2 mutations and decreased expression of tuberin in cultured tumor cells with an insertion mutation. | Feng JH | Human mutation | 2004 | PMID: 15024740 |
| SNP identification, haplotype analysis, and parental origin of mutations in TSC2. | Roberts PS | Human genetics | 2002 | PMID: 12136241 |
| TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/ TSC2 frequency ratios. | Langkau N | European journal of pediatrics | 2002 | PMID: 12111193 |
| Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. | Franz DN | American journal of respiratory and critical care medicine | 2001 | PMID: 11520734 |
| Tuberin phosphorylation regulates its interaction with hamartin. Two proteins involved in tuberous sclerosis. | Aicher LD | The Journal of biological chemistry | 2001 | PMID: 11290735 |
| Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. | Dabora SL | American journal of human genetics | 2001 | PMID: 11112665 |
| Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex. | Zhang H | Journal of human genetics | 1999 | PMID: 10570911 |
| Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis. | Niida Y | Human mutation | 1999 | PMID: 10533067 |
| Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. | Jones AC | American journal of human genetics | 1999 | PMID: 10205261 |
| Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients. | Au KS | American journal of human genetics | 1998 | PMID: 9463313 |
| The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis. | Maheshwar MM | Human molecular genetics | 1997 | PMID: 9302281 |
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Text-mined citations for rs45483392 ...
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Record last updated Oct 20, 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.