VCV000048971.21 - ClinVar

NM_000368.5(TSC1):c.2509_2512del (p.Asn837fs)

Germline

Classification

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.

(12)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000368.5(TSC1):c.2509_2512del (p.Asn837fs)

Variation ID: 48971 Accession: VCV000048971.21

Type and length

Deletion, 4 bp

Location

Cytogenetic: 9q34.13 9: 132900828-132900831 (GRCh38) [ NCBI UCSC ] 9: 135776215-135776218 (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	Sep 16, 2024	Mar 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000368.5:c.2509_2512del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000359.1:p.Asn837fs	frameshift
NM_000368.5:c.2509_2512delAACA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000368.4:c.2509_2512delAACA
NM_001162426.2:c.2506_2509del	NP_001155898.1:p.Asn836fs	frameshift
NM_001162427.2:c.2356_2359del	NP_001155899.1:p.Asn786fs	frameshift
NM_001362177.2:c.2146_2149del	NP_001349106.1:p.Asn716fs	frameshift
NC_000009.12:g.132900830_132900833del
NC_000009.11:g.135776217_135776220del
NG_012386.1:g.48803_48806del
LRG_486:g.48803_48806del

... more HGVS ... less HGVS

Protein change

N716fs, N837fs, N786fs, N836fs

Other names

Canonical SPDI

NC_000009.12:132900827:TGTTTG:TG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA006569 Tuberous sclerosis database (TSC1): TSC1_00170 Tuberous sclerosis database (TSC1): TSC1_00233 dbSNP: rs118203707 VarSome

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
Gene	OMIM	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.
TSC1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4843	4901

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.
Tuberous sclerosis syndrome	not provided (2)	no classification provided	-	RCV000042222.4
Tuberous sclerosis 1	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 19, 2023	RCV000201118.12
Cortical tubers Multiple renal cysts Seizure	Pathogenic (1)	criteria provided, single submitter	Mar 27, 2014	RCV000415443.2
not provided	Pathogenic (3)	criteria provided, single submitter	Mar 19, 2024	RCV000522266.8
Lymphangiomyomatosis	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2016	RCV001198554.2

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 (Jul 30, 2014)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	Tuberous sclerosis 1 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000255858.2 First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015	Publications: PubMed (3) PubMed: 10227394‚ 10363127‚ 9924605
Pathogenic (Mar 19, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000617401.5 First in ClinVar: Dec 19, 2017 Last updated: Sep 16, 2024	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14756965, 18032745, 15798777, 9924605, 17304050, 10227394, 10363127, 11112665, 32917966, 35253369, 31598950, 29286531, 32211034, 12015165) (less)
Pathogenic (Mar 27, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cortical tubers Multiple renal cysts Seizure Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000493038.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lymphangiomyomatosis Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369534.2 First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020	Comment: This variant was classified as: Pathogenic.
Pathogenic (Nov 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tuberous sclerosis 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002040742.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021
Pathogenic (Jan 10, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Tuberous sclerosis 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV003806582.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathogenic (Dec 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Tuberous sclerosis 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001399362.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 10227394‚ 17304050‚ 9924605‚ 29286531 Comment: This sequence change creates a premature translational stop signal (p.Asn837Valfs11) in the TSC1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Asn837Valfs11) in the TSC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 17304050). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis (PMID: 9924605, 29286531). This variant is also known as c.2729_2732delAAAC and c.2506_2509del. ClinVar contains an entry for this variant (Variation ID: 48971). 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	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807275.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
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: SCV001974546.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Jun 09, 2020)	no assertion criteria provided Method: clinical testing	Tuberous sclerosis 1 Affected status: yes Allele origin: germline	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University Accession: SCV001370506.1 First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020	Number of individuals with the variant: 1 Ethnicity/Population group: Japanese
not provided (-)	no classification provided (Tuberous Sclerosis Database Assertion Criteria 2015) Method: curation	TSC Affected status: yes Allele origin: germline	Tuberous sclerosis database (TSC1) Accession: SCV000066007.3 First in ClinVar: May 04, 2013 Last updated: Sep 16, 2013
not provided (-)	no classification provided (Tuberous Sclerosis Database Assertion Criteria 2015) Method: curation	TSC Affected status: yes Allele origin: germline	Tuberous sclerosis database (TSC1) Accession: SCV000066008.3 First in ClinVar: May 04, 2013 Last updated: Sep 16, 2013
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Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14756965, 18032745, 15798777, 9924605, 17304050, 10227394, 10363127, 11112665, 32917966, 35253369, 31598950, 29286531, 32211034, 12015165)

Comment:

This sequence change creates a premature translational stop signal (p.Asn837Valfs*11) in the TSC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 17304050). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis (PMID: 9924605, 29286531). This variant is also known as c.2729_2732delAAAC and c.2506_2509del. ClinVar contains an entry for this variant (Variation ID: 48971). 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice.	Tumienė B	Clinical genetics	2018	PMID: 29286531
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
Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation.	van Slegtenhorst M	Journal of medical genetics	1999	PMID: 10227394
Comprehensive mutation analysis of TSC1 using two-dimensional DNA electrophoresis with DGGE.	Dabora SL	Annals of human genetics	1998	PMID: 10363127
Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance.	Kwiatkowska J	Annals of human genetics	1998	PMID: 9924605

Text-mined citations for rs118203707 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_000368.5(TSC1):c.2509_2512del (p.Asn837fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs118203707 ...