NM_000548.5(TSC2):c.225+2T>C AND Tuberous sclerosis 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 14, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001035357.8

Allele description [Variation Report for NM_000548.5(TSC2):c.225+2T>C]

NM_000548.5(TSC2):c.225+2T>C

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.225+2T>C

HGVS:

NC_000016.10:g.2050488T>C
NG_005895.1:g.6183T>C
NG_008412.1:g.2379A>G
NM_000548.5:c.225+2T>CMANE SELECT
NM_001077183.3:c.225+2T>C
NM_001114382.3:c.225+2T>C
NM_001318827.2:c.225+2T>C
NM_001318829.2:c.78+2T>C
NM_001318831.2:c.-2+2T>C
NM_001318832.2:c.258+2T>C
NM_001363528.2:c.225+2T>C
NM_001370404.1:c.225+2T>C
NM_001370405.1:c.225+2T>C
NM_001406663.1:c.225+2T>C
NM_001406664.1:c.225+2T>C
NM_001406665.1:c.225+2T>C
NM_001406667.1:c.225+2T>C
NM_001406668.1:c.225+2T>C
NM_001406670.1:c.225+2T>C
NM_001406671.1:c.225+2T>C
NM_001406673.1:c.225+2T>C
NM_001406675.1:c.78+2T>C
NM_001406676.1:c.78+2T>C
NM_001406677.1:c.78+2T>C
NM_001406678.1:c.225+2T>C
NM_001406679.1:c.78+2T>C
NM_001406680.1:c.-592+2T>C
NM_001406681.1:c.-221+2T>C
NM_001406682.1:c.-2+2T>C
NM_001406683.1:c.-592+2T>C
NM_001406684.1:c.-2+2T>C
NM_001406685.1:c.-2+2T>C
NM_001406686.1:c.-2+2T>C
NM_001406687.1:c.-592+2T>C
NM_001406688.1:c.-2+2T>C
NM_001406689.1:c.-1207+2T>C
NM_001406690.1:c.-1207+2T>C
NM_001406691.1:c.-1207+2T>C
NM_001406692.1:c.-1207+2T>C
NM_001406693.1:c.-1513+2T>C
NM_001406694.1:c.-1088+2T>C
NM_001406695.1:c.-1088+2T>C
NM_001406696.1:c.-1195+2T>C
NM_001406697.1:c.-1207+2T>C
NM_001406698.1:c.-1383+2T>C
NM_021055.3:c.225+2T>C
LRG_487t1:c.225+2T>C
LRG_1366:g.2379A>G
LRG_487:g.6183T>C
NC_000016.9:g.2100489T>C
NM_000548.3:c.225+2T>C

Links:

dbSNP: rs397515105

NCBI 1000 Genomes Browser:

rs397515105

Molecular consequence:

NM_000548.5:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001077183.3:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001114382.3:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001318827.2:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001318829.2:c.78+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001318831.2:c.-2+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001318832.2:c.258+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001363528.2:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370404.1:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370405.1:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406663.1:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406664.1:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406665.1:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406667.1:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406668.1:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406670.1:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406671.1:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406673.1:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406675.1:c.78+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406676.1:c.78+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406677.1:c.78+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406678.1:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406679.1:c.78+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406680.1:c.-592+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406681.1:c.-221+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406682.1:c.-2+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406683.1:c.-592+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406684.1:c.-2+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406685.1:c.-2+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406686.1:c.-2+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406687.1:c.-592+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406688.1:c.-2+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406689.1:c.-1207+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406690.1:c.-1207+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406691.1:c.-1207+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406692.1:c.-1207+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406693.1:c.-1513+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406694.1:c.-1088+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406695.1:c.-1088+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406696.1:c.-1195+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406697.1:c.-1207+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406698.1:c.-1383+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_021055.3:c.225+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001198682	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 14, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 10205261, 17304050, 28492532
SCV001427097	Clinical Genomics Laboratory, Stanford Medicine	no assertion criteria provided	Likely pathogenic (Nov 14, 2019)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001198682

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 14, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001427097

Clinical Genomics Laboratory, Stanford Medicine

no assertion criteria provided

Likely pathogenic
(Nov 14, 2019)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	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 (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001198682.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change affects a donor splice site in intron 3 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). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 834629). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Clinical Genomics Laboratory, Stanford Medicine, SCV001427097.1

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

Description

The c.225+2T>C variant in the TSC2 gene has not been previously reported in association with disease and was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant alters the canonical donor splice site in intron 3, which is predicted to result in abnormal gene splicing. Notably, a different nucleotide change at this position (c.225+2T>A) has been previously reported de novo in an individual with features of tuberous sclerosis complex (Nellist et al., 2015), suggesting the c.225+2T>C variant may similarly be associated with tuberous sclerosis complex. Heterozygous loss of function is an established mechanism of disease for the TSC2 gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.225+2T>C variant as likely pathogenic for tuberous sclerosis complex in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PVS1_Strong; PM2]

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

Last Updated: Oct 8, 2024

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