VCV000049660.64 - ClinVar

NM_000548.5(TSC2):c.1378G>A (p.Ala460Thr)

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_000548.5(TSC2):c.1378G>A (p.Ala460Thr)

Variation ID: 49660 Accession: VCV000049660.64

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 2062988 (GRCh38) [ NCBI UCSC ] 16: 2112989 (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	Jun 9, 2014	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000548.5:c.1378G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000539.2:p.Ala460Thr	missense
NM_001077183.3:c.1378G>A	NP_001070651.1:p.Ala460Thr	missense
NM_001114382.3:c.1378G>A	NP_001107854.1:p.Ala460Thr	missense
NM_001318827.2:c.1267G>A	NP_001305756.1:p.Ala423Thr	missense
NM_001318829.2:c.1231G>A	NP_001305758.1:p.Ala411Thr	missense
NM_001318831.2:c.778G>A	NP_001305760.1:p.Ala260Thr	missense
NM_001318832.2:c.1411G>A	NP_001305761.1:p.Ala471Thr	missense
NM_001363528.2:c.1378G>A	NP_001350457.1:p.Ala460Thr	missense
NM_001370404.1:c.1378G>A	NP_001357333.1:p.Ala460Thr	missense
NM_001370405.1:c.1378G>A	NP_001357334.1:p.Ala460Thr	missense
NM_021055.3:c.1378G>A	NP_066399.2:p.Ala460Thr	missense
NC_000016.10:g.2062988G>A
NC_000016.9:g.2112989G>A
NG_005895.1:g.18683G>A
LRG_487:g.18683G>A
LRG_487t1:c.1378G>A

... more HGVS ... less HGVS

Protein change

A460T, A423T, A411T, A471T, A260T

Other names

Canonical SPDI

NC_000016.10:2062987: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.

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

The Genome Aggregation Database (gnomAD) 0.00068

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00080

Trans-Omics for Precision Medicine (TOPMed) 0.00087

The Genome Aggregation Database (gnomAD), exomes 0.00125

Exome Aggregation Consortium (ExAC) 0.00241

Links

ClinGen: CA014629 Tuberous sclerosis database (TSC2): TSC2_01096 dbSNP: rs137854154 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.
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.
Tuberous sclerosis syndrome	Likely benign (3)	criteria provided, single submitter	Feb 12, 2018	RCV000042922.11
not specified	Benign/Likely benign (8)	criteria provided, multiple submitters, no conflicts	Oct 7, 2021	RCV000122206.18
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000204918.34
Hereditary cancer-predisposing syndrome	Benign (2)	criteria provided, multiple submitters, no conflicts	May 10, 2020	RCV000130880.5
Tuberous sclerosis 2	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000989417.15

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 (Feb 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Tuberous sclerosis syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000395580.3 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 (Jun 28, 2021)	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: SCV001748775.1 First in ClinVar: Jul 10, 2021 Last updated: Jul 10, 2021	Comment: Variant summary: TSC2 c.1378G>A (p.Ala460Thr) results in a non-conservative amino acid change located in the Tuberin, N-terminal domain of the encoded protein sequence. Three of … (more) Variant summary: TSC2 c.1378G>A (p.Ala460Thr) results in a non-conservative amino acid change located in the Tuberin, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 155816 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 18.11 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1378G>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
Likely benign (Aug 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: SCV001150690.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: TSC2: BS2 Number of individuals with the variant: 63
Benign (Apr 25, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000540600.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.5% (46/8536) European chromosomes; ClinVar: 2 labs classify as LB. 3/5 pubs describe as nonpathogenic. (less) Method: Genome/Exome Filtration
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Tuberous sclerosis 2 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139739.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Nov 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tuberous sclerosis 2 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002041333.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021
Likely benign (Oct 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002069942.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Likely benign (Jan 24, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004564857.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024
Benign (Aug 20, 2015)	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: SCV000185785.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 19258292‚ 21309039‚ 24728327‚ 25281918 Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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 (Oct 21, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000336111.4 First in ClinVar: Dec 06, 2016 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSC2 Number of individuals with the variant: 1 Sex: mixed
Benign (May 10, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002532780.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Nov 08, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001940283.2 First in ClinVar: Sep 29, 2021 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 25281918, 25637381, 21309039, 24728327, 19258292, 27884173)
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tuberous sclerosis 2 Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004016114.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Sep 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tuberous sclerosis 2 Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004360862.1 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 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000261891.12 First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024
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: SCV005216969.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
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: SCV001925923.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (Jun 01, 2014)	no assertion criteria provided Method: research	Tuberous sclerosis (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190665.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Benign (Feb 05, 2020)	no assertion criteria provided Method: clinical testing	Tuberous sclerosis 2 Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001190850.1 First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020
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: SCV001808527.1 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 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: SCV001975849.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000086427.1 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
not provided (-)	no classification provided (Tuberous Sclerosis Database Assertion Criteria 2015) Method: curation	TSC Affected status: yes Allele origin: germline	Tuberous sclerosis database (TSC2) Accession: SCV000066719.3 First in ClinVar: May 04, 2013 Last updated: Dec 06, 2014
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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:

Variant summary: TSC2 c.1378G>A (p.Ala460Thr) results in a non-conservative amino acid change located in the Tuberin, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 155816 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 18.11 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1378G>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.5% (46/8536) European chromosomes; ClinVar: 2 labs classify as LB. 3/5 pubs describe as nonpathogenic.

Comment:

This alteration is classified as 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
The analysis of mutations and exon deletions at TSC2 gene in angiomyolipomas associated with tuberous sclerosis complex.	Yang HM	Experimental and molecular pathology	2014	PMID: 25281918
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
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
Unusual radiological presentation of tuberous sclerosis complex with leptomeningeal angiomatosis associated with a hypomorphic mutation in the TSC2 gene.	Ramantani G	Journal of child neurology	2009	PMID: 19258292
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSC2	-	-	-	-

Text-mined citations for rs137854154 ...

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_000548.5(TSC2):c.1378G>A (p.Ala460Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137854154 ...