NM_000548.5(TSC2):c.4662+1G>A AND Tuberous sclerosis 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003511998.3

Allele description [Variation Report for NM_000548.5(TSC2):c.4662+1G>A]

NM_000548.5(TSC2):c.4662+1G>A

Gene:

TSC2:TSC complex subunit 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000548.5(TSC2):c.4662+1G>A

HGVS:

NC_000016.10:g.2085323G>A
NG_005895.1:g.41018G>A
NM_000548.5:c.4662+1G>AMANE SELECT
NM_001077183.3:c.4461+1G>A
NM_001114382.3:c.4593+1G>A
NM_001318827.2:c.4353+1G>A
NM_001318829.2:c.4317+1G>A
NM_001318831.2:c.3930+1G>A
NM_001318832.2:c.4494+1G>A
NM_001363528.2:c.4464+1G>A
NM_001370404.1:c.4530+1G>A
NM_001370405.1:c.4533+1G>A
NM_001406663.1:c.4659+1G>A
NM_001406664.1:c.4590+1G>A
NM_001406665.1:c.4584+1G>A
NM_001406667.1:c.4554+1G>A
NM_001406668.1:c.4551+1G>A
NM_001406670.1:c.4482+1G>A
NM_001406671.1:c.4452+1G>A
NM_001406673.1:c.4449+1G>A
NM_001406675.1:c.4446+1G>A
NM_001406676.1:c.4443+1G>A
NM_001406677.1:c.4404+1G>A
NM_001406678.1:c.4350+1G>A
NM_001406679.1:c.4314+1G>A
NM_001406680.1:c.4062+1G>A
NM_001406681.1:c.4002+1G>A
NM_001406682.1:c.3993+1G>A
NM_001406683.1:c.3993+1G>A
NM_001406684.1:c.3990+1G>A
NM_001406685.1:c.3864+1G>A
NM_001406686.1:c.3864+1G>A
NM_001406687.1:c.3861+1G>A
NM_001406688.1:c.3861+1G>A
NM_001406689.1:c.3249+1G>A
NM_001406690.1:c.3189+1G>A
NM_001406691.1:c.3186+1G>A
NM_001406692.1:c.3120+1G>A
NM_001406693.1:c.3120+1G>A
NM_001406694.1:c.3120+1G>A
NM_001406695.1:c.3117+1G>A
NM_001406696.1:c.3117+1G>A
NM_001406697.1:c.3117+1G>A
NM_001406698.1:c.2859+1G>A
NM_021055.3:c.4533+1G>A
LRG_487t1:c.4662+1G>A
LRG_487:g.41018G>A
NC_000016.9:g.2135324G>A
NM_000548.3:c.4662+1G>A
p.?

Links:

Tuberous sclerosis database (TSC2): TSC2_00864; dbSNP: rs45514095

NCBI 1000 Genomes Browser:

rs45514095

Molecular consequence:

NM_000548.5:c.4662+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001077183.3:c.4461+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001114382.3:c.4593+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001318827.2:c.4353+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001318829.2:c.4317+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001318831.2:c.3930+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001318832.2:c.4494+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001363528.2:c.4464+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370404.1:c.4530+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370405.1:c.4533+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406663.1:c.4659+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406664.1:c.4590+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406665.1:c.4584+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406667.1:c.4554+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406668.1:c.4551+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406670.1:c.4482+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406671.1:c.4452+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406673.1:c.4449+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406675.1:c.4446+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406676.1:c.4443+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406677.1:c.4404+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406678.1:c.4350+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406679.1:c.4314+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406680.1:c.4062+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406681.1:c.4002+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406682.1:c.3993+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406683.1:c.3993+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406684.1:c.3990+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406685.1:c.3864+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406686.1:c.3864+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406687.1:c.3861+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406688.1:c.3861+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406689.1:c.3249+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406690.1:c.3189+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406691.1:c.3186+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406692.1:c.3120+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406693.1:c.3120+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406694.1:c.3120+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406695.1:c.3117+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406696.1:c.3117+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406697.1:c.3117+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406698.1:c.2859+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_021055.3:c.4533+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Tuberous sclerosis 2 (TSC2)
Identifiers:: MONDO: MONDO:0013199; MedGen: C1860707; Orphanet: 805; OMIM: 613254

Recent activity

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mitochondrial carnitine/acylcarnitine carrier-like protein [Lactuca sativa]
mitochondrial carnitine/acylcarnitine carrier-like protein [Lactuca sativa]
gi|1340510890|ref|XP_023736247.1|

Protein
S41 family peptidase [Caldicellulosiruptor danielii]
S41 family peptidase [Caldicellulosiruptor danielii]
gi|2634142572|gnl|extdb|SOJ16_00179 WPX07950.1|

Protein
SLC25A20 [Chelonoidis abingdonii]
SLC25A20 [Chelonoidis abingdonii]
Gene ID:116825640

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004296678	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 14, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16199547, 10205261, 17304050, 27859028, 28492532
SCV005368076	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 8, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004296678

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 14, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV005368076

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 8, 2024)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.

Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP.

Am J Hum Genet. 1999 May;64(5):1305-15. Review.

PubMed [citation]

PMID:: 10205261
PMCID:: PMC1377866

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004296678.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

ClinVar contains an entry for this variant (Variation ID: 50031). This sequence change affects a donor splice site in intron 36 of the TSC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with tuberous sclerosis complex (PMID: 27859028). In at least one individual the variant was observed to be de novo. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV005368076.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Criteria applied: PVS1,PS4_MOD,PM2_SUP

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

ClinVar

Relating variation to medicine