For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49304). This premature translational stop signal has been observed in individuals with tuberous sclerosis (PMID: 9302281, 11112665, 12111193, 15595939, 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn1515Serfs*60) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050).
ClinVar Genomic variation as it relates to human health
NM_000548.5(TSC2):c.4544_4547del (p.Asn1515fs)
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.
(10)
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
10
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.4544_4547del (p.Asn1515fs)
Variation ID: 49304 Accession: VCV000049304.18
- Type and length
-
Deletion, 4 bp
- Location
-
Cytogenetic: 16p13.3 16: 2084998-2085001 (GRCh38) [ NCBI UCSC ] 16: 2134999-2135002 (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 May 1, 2024 Sep 15, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000548.5:c.4544_4547del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000539.2:p.Asn1515fs frameshift NM_000548.5:c.4544_4547delACAA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000548.3:c.4544_4547delACAA NM_001077183.3:c.4343_4346del NP_001070651.1:p.Asn1448fs frameshift NM_001114382.3:c.4475_4478del NP_001107854.1:p.Asn1492fs frameshift NM_001318827.2:c.4235_4238del NP_001305756.1:p.Asn1412fs frameshift NM_001318829.2:c.4199_4202del NP_001305758.1:p.Asn1400fs frameshift NM_001318831.2:c.3812_3815del NP_001305760.1:p.Asn1271fs frameshift NM_001318832.2:c.4376_4379del NP_001305761.1:p.Asn1459fs frameshift NM_001363528.2:c.4346_4349del NP_001350457.1:p.Asn1449fs frameshift NM_001370404.1:c.4412_4415del NP_001357333.1:p.Asn1471fs frameshift NM_001370405.1:c.4415_4418del NP_001357334.1:p.Asn1472fs frameshift NM_021055.3:c.4415_4418del NP_066399.2:p.Asn1472fs frameshift NC_000016.10:g.2085001_2085004del NC_000016.9:g.2135002_2135005del NG_005895.1:g.40696_40699del LRG_487:g.40696_40699del - Protein change
- N1271fs, N1449fs, N1515fs, N1472fs, N1400fs, N1448fs, N1459fs, N1492fs, N1412fs, N1471fs
- Other names
-
p.Asn1515Serfs*60
- Canonical SPDI
- NC_000016.10:2084997:CAAACAA:CAA
-
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 |
10754 | 10953 | |
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 (2) |
no classification provided
|
- | RCV000042563.4 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 15, 2023 | RCV000201030.15 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 21, 2023 | RCV000360616.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 3, 2017 | RCV002336156.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 19, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000255903.2
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015 |
|
|
|
Pathogenic
(Jun 21, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000709284.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Sep 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tuberous sclerosis 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000285408.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49304). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49304). This premature translational stop signal has been observed in individuals with tuberous sclerosis (PMID: 9302281, 11112665, 12111193, 15595939, 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn1515Serfs*60) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). (less)
|
|
|
Pathogenic
(Oct 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002636558.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.4544_4547delACAA pathogenic mutation, located in coding exon 34 of the TSC2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4544 to … (more)
The c.4544_4547delACAA pathogenic mutation, located in coding exon 34 of the TSC2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4544 to 4547, causing a translational frameshift with a predicted alternate stop codon (p.N1515Sfs*60). This pathogenic mutation has been reported in multiple individuals diagnosed with tuberous sclerosis complex (TSC) (Ali M et al. Acta Neurol. Scand. 2005 Jan;111:54-63; Au KS et al. Genet. Med., 2007 Feb;9:88-100). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Jun 21, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329788.6
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Comment:
The c.4544_4547delACAA pathogenic variant in the TSC2 gene has been reported previously multiple times in association with tuberous sclerosis complex (Maheshwar et al., 1997, Ali … (more)
The c.4544_4547delACAA pathogenic variant in the TSC2 gene has been reported previously multiple times in association with tuberous sclerosis complex (Maheshwar et al., 1997, Ali et al., 2005, TSC2 LOVD). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The deletion causes a frameshift starting with codon Asparagine 1515, changes this amino acid to a Serine residue and creates a premature Stop codon at position 60 of the new reading frame, denoted p.Asn1515SerfsX60. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. (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: SCV002041000.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
|
|
|
Pathogenic
(Feb 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224079.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP4, PM2, PS4_moderate, PVS1
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jun 11, 2020)
|
no assertion criteria provided
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: SCV001364437.1
First in ClinVar: Jun 29, 2020 Last updated: Jun 29, 2020 |
Number of individuals with the variant: 1
Ethnicity/Population group: Japanese
|
|
|
not provided
(-)
|
no classification provided
Method: curation
|
TSC
Affected status: yes
Allele origin:
germline
|
Tuberous sclerosis database (TSC2)
Accession: SCV000066357.3
First in ClinVar: May 04, 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: SCV000066356.3
First in ClinVar: May 04, 2013 Last updated: Sep 16, 2013 |
|
Comment:
Comment:
The c.4544_4547delACAA pathogenic mutation, located in coding exon 34 of the TSC2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4544 to 4547, causing a translational frameshift with a predicted alternate stop codon (p.N1515Sfs*60). This pathogenic mutation has been reported in multiple individuals diagnosed with tuberous sclerosis complex (TSC) (Ali M et al. Acta Neurol. Scand. 2005 Jan;111:54-63; Au KS et al. Genet. Med., 2007 Feb;9:88-100). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
The c.4544_4547delACAA pathogenic variant in the TSC2 gene has been reported previously multiple times in association with tuberous sclerosis complex (Maheshwar et al., 1997, Ali et al., 2005, TSC2 LOVD). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The deletion causes a frameshift starting with codon Asparagine 1515, changes this amino acid to a Serine residue and creates a premature Stop codon at position 60 of the new reading frame, denoted p.Asn1515SerfsX60. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Comment:
PP4, PM2, PS4_moderate, PVS1
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:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49304). This premature translational stop signal has been observed in individuals with tuberous sclerosis (PMID: 9302281, 11112665, 12111193, 15595939, 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn1515Serfs*60) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050).
Comment:
The c.4544_4547delACAA pathogenic mutation, located in coding exon 34 of the TSC2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4544 to 4547, causing a translational frameshift with a predicted alternate stop codon (p.N1515Sfs*60). This pathogenic mutation has been reported in multiple individuals diagnosed with tuberous sclerosis complex (TSC) (Ali M et al. Acta Neurol. Scand. 2005 Jan;111:54-63; Au KS et al. Genet. Med., 2007 Feb;9:88-100). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
The c.4544_4547delACAA pathogenic variant in the TSC2 gene has been reported previously multiple times in association with tuberous sclerosis complex (Maheshwar et al., 1997, Ali et al., 2005, TSC2 LOVD). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The deletion causes a frameshift starting with codon Asparagine 1515, changes this amino acid to a Serine residue and creates a premature Stop codon at position 60 of the new reading frame, denoted p.Asn1515SerfsX60. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Comment:
PP4, PM2, PS4_moderate, PVS1
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of Clinical Features and Next-Generation Sequencing of 12 Tuberous Sclerosis Families in China. | Wang X | Frontiers in medicine | 2022 | PMID: 35712104 |
| Electro-clinical and neurodevelopmental outcome in six children with early diagnosis of tuberous sclerosis complex and role of the genetic background. | Savini MN | Italian journal of pediatrics | 2020 | PMID: 32216820 |
| 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 |
| Mutation and polymorphism analysis of TSC1 and TSC2 genes in Indian patients with tuberous sclerosis complex. | Ali M | Acta neurologica Scandinavica | 2005 | PMID: 15595939 |
| 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 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 |
| Analysis of all exons of TSC1 and TSC2 genes for germline mutations in Japanese patients with tuberous sclerosis: report of 10 mutations. | Yamashita Y | American journal of medical genetics | 2000 | PMID: 10607950 |
| 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 |
| 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 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSC2 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs137854175 ...
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.