VCV000041686.43 - ClinVar

NM_000368.5(TSC1):c.1001C>T (p.Ser334Leu)

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.

(20)

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.

Benign/Likely benign

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.1001C>T (p.Ser334Leu)

Variation ID: 41686 Accession: VCV000041686.43

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.13 9: 132911481 (GRCh38) [ NCBI UCSC ] 9: 135786868 (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	Apr 12, 2013	Oct 20, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000368.5:c.1001C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000359.1:p.Ser334Leu	missense
NM_001162426.2:c.1001C>T	NP_001155898.1:p.Ser334Leu	missense
NM_001162427.2:c.848C>T	NP_001155899.1:p.Ser283Leu	missense
NM_001362177.2:c.638C>T	NP_001349106.1:p.Ser213Leu	missense
NC_000009.12:g.132911481G>A
NC_000009.11:g.135786868G>A
NG_012386.1:g.38153C>T
LRG_486:g.38153C>T
LRG_486t1:c.1001C>T	LRG_486p1:p.Ser334Leu

... more HGVS ... less HGVS

Protein change

S334L, S213L, S283L

Other names

Canonical SPDI

NC_000009.12:132911480:G:A

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.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00012

Trans-Omics for Precision Medicine (TOPMed) 0.00014

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

The Genome Aggregation Database (gnomAD), exomes 0.00043

Exome Aggregation Consortium (ExAC) 0.00045

Links

ClinGen: CA004276 Tuberous sclerosis database (TSC1): TSC1_00279 dbSNP: rs118203481 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	4848	4906

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	Benign (2)	criteria provided, single submitter	Feb 5, 2024	RCV000054847.7
not provided	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Apr 1, 2023	RCV000034598.23
not specified	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jan 31, 2018	RCV000122200.12
Hereditary cancer-predisposing syndrome	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Dec 9, 2020	RCV000572872.5
Isolated focal cortical dysplasia type II	Likely benign (1)	criteria provided, single submitter	Apr 28, 2017	RCV000398057.6
Isolated focal cortical dysplasia type II Lymphangiomyomatosis Tuberous sclerosis 1	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jul 12, 2022	RCV002490461.2
TSC1-related disorder	Likely benign (1)	no assertion criteria provided	Mar 14, 2019	RCV003944882.2
Tuberous sclerosis 1	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV001080188.13

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.
Likely benign (Sep 10, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000153104.2 First in ClinVar: May 17, 2014 Last updated: Oct 05, 2015
Benign (Jan 31, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000527394.3 First in ClinVar: Mar 08, 2017 Last updated: Apr 09, 2018	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (Oct 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tuberous sclerosis 1 Lymphangiomyomatosis Isolated focal cortical dysplasia type II Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002799201.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Jan 31, 2024)	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: SCV000284662.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024
Likely benign (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Tuberous sclerosis 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000478246.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 21624971‚ 19747374‚ 23514105 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Isolated focal cortical dysplasia type II Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000478245.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Oct 18, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004221379.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (3) PubMed: 23514105‚ 21309039‚ 19747374
Likely benign (Apr 05, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000675346.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 19747374‚ 21309039 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Apr 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004156654.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: TSC1: BP4, BS1 Number of individuals with the variant: 2
Benign (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tuberous sclerosis syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004840501.1 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)	Number of individuals with the variant: 41
Likely benign (Jul 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Isolated focal cortical dysplasia type II Tuberous sclerosis 1 Lymphangiomyomatosis Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003920597.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: TSC1 NM_000368.4 exon 10 p.Ser334Leu (c.1001C>T): This variant has been reported in the literature in at least 1 individual with nonalcoholic fatty liver disease (Pelusi … (more) TSC1 NM_000368.4 exon 10 p.Ser334Leu (c.1001C>T): This variant has been reported in the literature in at least 1 individual with nonalcoholic fatty liver disease (Pelusi 2019 PMID:30842500). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.01% (13/67998) (https://gnomad.broadinstitute.org/variant/9-132911481-G-A?dataset=gnomad_r3)). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:41686). This variant amino acid Leucine (Leu) is present in multiple species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. (less)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005225986.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (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: SCV002040478.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021
Likely benign (Dec 09, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002530870.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
variant of unknown significance (Jul 13, 2012)	no assertion criteria provided Method: research	not provided Affected status: no Allele origin: germline	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043518.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013	Publications: PubMed (1) PubMed: 22703879 Comment: Converted during submission to Uncertain significance. Number of individuals with the variant: 1 Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
Likely benign (Mar 14, 2019)	no assertion criteria provided Method: clinical testing	TSC1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004775245.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001966265.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely benign (-)	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: SCV001741806.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
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: SCV000065752.3 First in ClinVar: May 03, 2013 Last updated: Sep 16, 2013
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000086419.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

TSC1 NM_000368.4 exon 10 p.Ser334Leu (c.1001C>T): This variant has been reported in the literature in at least 1 individual with nonalcoholic fatty liver disease (Pelusi 2019 PMID:30842500). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.01% (13/67998) (https://gnomad.broadinstitute.org/variant/9-132911481-G-A?dataset=gnomad_r3)). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:41686). This variant amino acid Leucine (Leu) is present in multiple species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.

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 variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder.	Bahl S	Molecular autism	2013	PMID: 23514105
Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.	Schaaf CP	Human molecular genetics	2011	PMID: 21624971
Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex.	Hoogeveen-Westerveld M	Human mutation	2011	PMID: 21309039
Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex.	Mozaffari M	BMC medical genetics	2009	PMID: 19747374

Text-mined citations for rs118203481 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000368.5(TSC1):c.1001C>T (p.Ser334Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs118203481 ...