VCV000041724.58 - ClinVar

NM_000548.5(TSC2):c.1070C>T (p.Ala357Val)

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.

(17)

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.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(5); Likely benign(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000548.5(TSC2):c.1070C>T (p.Ala357Val)

Variation ID: 41724 Accession: VCV000041724.58

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 2060764 (GRCh38) [ NCBI UCSC ] 16: 2110765 (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	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000548.5:c.1070C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000539.2:p.Ala357Val	missense
NM_001077183.3:c.1070C>T	NP_001070651.1:p.Ala357Val	missense
NM_001114382.3:c.1070C>T	NP_001107854.1:p.Ala357Val	missense
NM_001318827.2:c.959C>T	NP_001305756.1:p.Ala320Val	missense
NM_001318829.2:c.923C>T	NP_001305758.1:p.Ala308Val	missense
NM_001318831.2:c.470C>T	NP_001305760.1:p.Ala157Val	missense
NM_001318832.2:c.1103C>T	NP_001305761.1:p.Ala368Val	missense
NM_001363528.2:c.1070C>T	NP_001350457.1:p.Ala357Val	missense
NM_001370404.1:c.1070C>T	NP_001357333.1:p.Ala357Val	missense
NM_001370405.1:c.1070C>T	NP_001357334.1:p.Ala357Val	missense
NM_021055.3:c.1070C>T	NP_066399.2:p.Ala357Val	missense
NC_000016.10:g.2060764C>T
NC_000016.9:g.2110765C>T
NG_005895.1:g.16459C>T
LRG_487:g.16459C>T
LRG_487t1:c.1070C>T

... more HGVS ... less HGVS

Protein change

A357V, A308V, A320V, A157V, A368V

Other names

Canonical SPDI

NC_000016.10:2060763:C:T

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.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

Trans-Omics for Precision Medicine (TOPMed) 0.00034

The Genome Aggregation Database (gnomAD), exomes 0.00043

Exome Aggregation Consortium (ExAC) 0.00047

The Genome Aggregation Database (gnomAD) 0.00050

Links

Tuberous sclerosis database (TSC2): TSC2_02016 dbSNP: rs150195368 ClinGen: CA013675 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.
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000034641.38
Tuberous sclerosis syndrome	not provided (1)	no classification provided	-	RCV000055595.9
not specified	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jul 1, 2020	RCV000122202.21
Tuberous sclerosis 2	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Feb 1, 2024	RCV000230505.26
Hereditary cancer-predisposing syndrome	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Aug 2, 2021	RCV000163628.11
Isolated focal cortical dysplasia type II	Uncertain significance (1)	criteria provided, single submitter	Aug 7, 2018	RCV000714826.10

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 (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002011359.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Uncertain significance (Aug 07, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tuberous sclerosis 2 Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000845562.1 First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018	Number of individuals with the variant: 1 Sex: female Geographic origin: Iran
Uncertain significance (Aug 07, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Focal cortical dysplasia type II Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000845563.1 First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018	Number of individuals with the variant: 1 Sex: female Geographic origin: Iran
Likely benign (Oct 31, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000702129.2 First in ClinVar: Dec 19, 2017 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
Likely benign (Jul 01, 2020)	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: SCV000205284.6 First in ClinVar: Jan 31, 2015 Last updated: May 29, 2021	Publications: PubMed (2) PubMed: 22903760‚ 21309039 Comment: The p.Ala357Val variant in TSC2 has been reported in 2 individuals with Tuberous Sclerosis-2 (Peron 2018 PMID: 29432982). It has also been identified in 0.092% … (more) The p.Ala357Val variant in TSC2 has been reported in 2 individuals with Tuberous Sclerosis-2 (Peron 2018 PMID: 29432982). It has also been identified in 0.092% (23/25098) (1 homozygote) Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 41724). Functional studies indicate that this variant may not impact protein function (Hoogevenn-Westerveld 2011 PMID: 21309039). However, this in vitro assay may not accurately represent biological function. In addition, computational prediction tools and conservation analysis suggest that the Ala357Val variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: PS4_Moderate, BS1_Supporting. (less) Number of individuals with the variant: 1
Likely benign (Aug 02, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002532742.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Jun 09, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000515014.6 First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 21309039, 22703879, 23514105, 24728327, 22558107, 25801821, 24356096, 24631838, 22885699, 26580448, 29432982)
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: SCV000285220.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024
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: SCV001150684.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: TSC2: BP4, BS2 Number of individuals with the variant: 21
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: SCV002041125.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021
Benign (Oct 09, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Tuberous sclerosis 2 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004189644.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence … (more) This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. (less)
Benign (Nov 19, 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: SCV000214196.7 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	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)
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: SCV000043524.1 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: 2 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 (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800689.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001921010.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000086422.1 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: SCV000083820.2 First in ClinVar: Sep 16, 2013 Last updated: Sep 16, 2013
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Comment:

The p.Ala357Val variant in TSC2 has been reported in 2 individuals with Tuberous Sclerosis-2 (Peron 2018 PMID: 29432982). It has also been identified in 0.092% (23/25098) (1 homozygote) Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 41724). Functional studies indicate that this variant may not impact protein function (Hoogevenn-Westerveld 2011 PMID: 21309039). However, this in vitro assay may not accurately represent biological function. In addition, computational prediction tools and conservation analysis suggest that the Ala357Val variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: PS4_Moderate, BS1_Supporting.

Comment:

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.

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
Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex.	Hoogeveen-Westerveld M	Human mutation	2013	PMID: 22903760
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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TSC2	-	-	-	-

Text-mined citations for rs150195368 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000548.5(TSC2):c.1070C>T (p.Ala357Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs150195368 ...