VCV000049008.86 - ClinVar

NM_000368.5(TSC1):c.2865C>T (p.Thr955=)

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.

(23)

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.2865C>T (p.Thr955=)

Variation ID: 49008 Accession: VCV000049008.86

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.13 9: 132897294 (GRCh38) [ NCBI UCSC ] 9: 135772681 (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	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000368.5:c.2865C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000359.1:p.Thr955=	synonymous
NM_001162426.2:c.2862C>T	NP_001155898.1:p.Thr954=	synonymous
NM_001162427.2:c.2712C>T	NP_001155899.1:p.Thr904=	synonymous
NM_001362177.2:c.2502C>T	NP_001349106.1:p.Thr834=	synonymous
NC_000009.12:g.132897294G>A
NC_000009.11:g.135772681G>A
NG_012386.1:g.52340C>T
LRG_486:g.52340C>T
LRG_486t1:c.2865C>T	LRG_486p1:p.Thr955=

... more HGVS ... less HGVS

Protein change

Other names

p.T955T:ACC>ACT

Canonical SPDI

NC_000009.12:132897293: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.

0.00120 (A)

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

1000 Genomes Project 0.00120

1000 Genomes Project 30x 0.00141

The Genome Aggregation Database (gnomAD), exomes 0.00161

Exome Aggregation Consortium (ExAC) 0.00166

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00185

Trans-Omics for Precision Medicine (TOPMed) 0.00192

The Genome Aggregation Database (gnomAD) 0.00193

Links

ClinGen: CA007079 Tuberous sclerosis database (TSC1): TSC1_00283 dbSNP: rs45468995 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	4844	4902

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 1	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000205209.28
Isolated focal cortical dysplasia type II	Benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV000274884.13
Tuberous sclerosis syndrome	Likely benign (2)	criteria provided, single submitter	Feb 5, 2024	RCV000042259.15
Hereditary cancer-predisposing syndrome	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jul 31, 2020	RCV000163343.11
not specified	Benign/Likely benign (10)	criteria provided, multiple submitters, no conflicts	Jan 2, 2023	RCV000152157.30
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV001725957.33
Isolated focal cortical dysplasia type II Lymphangiomyomatosis Tuberous sclerosis 1	Likely benign (1)	criteria provided, single submitter	Jul 26, 2021	RCV002496670.8

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.
Benign (May 31, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	Tuberous sclerosis 1 Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000677529.1 First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018
Benign (Oct 08, 2013)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000169095.12 First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016	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 (Feb 21, 2013)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000200857.5 First in ClinVar: Jan 30, 2015 Last updated: May 03, 2018	Comment: Thr955Thr in exon 22 of TSC1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue … (more) Thr955Thr in exon 22 of TSC1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.2% (20/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs45468995). (less) Number of individuals with the variant: 1
Benign (Jan 12, 2018)	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: SCV000478188.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 12, 2018)	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: SCV000478187.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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: SCV002040355.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021
Likely benign (Jul 26, 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: SCV002805453.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely 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: SCV004840453.1 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: 541
Likely benign (Nov 04, 2014)	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: SCV000213877.8 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	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)
Benign (Jul 01, 2024)	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: SCV001962584.20 First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024	Comment: TSC1: BP4, BP7, BS1, BS2 Number of individuals with the variant: 33
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303867.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Jul 29, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227886.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSC1 Number of individuals with the variant: 2 Sex: mixed
Benign (Jul 31, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002528903.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (May 14, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002774054.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 10533067
Benign (Apr 19, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001474484.3 First in ClinVar: Jan 26, 2021 Last updated: Mar 04, 2023
Benign (Jan 02, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003800740.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023
Likely benign (Mar 29, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tuberous sclerosis 1 Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004360802.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
Benign (Feb 01, 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: SCV000262139.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928743.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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: SCV001968223.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808514.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921850.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 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: SCV000066046.3 First in ClinVar: May 04, 2013 Last updated: Sep 16, 2013
click to load more click to collapse

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:

Thr955Thr in exon 22 of TSC1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.2% (20/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs45468995).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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.

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
Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis.	Niida Y	Human mutation	1999	PMID: 10533067
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSC1	-	-	-	-

Text-mined citations for rs45468995 ...

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 Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_000368.5(TSC1):c.2865C>T (p.Thr955=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs45468995 ...