NM_000548.5(TSC2):c.515dup (p.Leu172fs) AND Tuberous sclerosis 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 22, 2022
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:: RCV003026299.2

Allele description [Variation Report for NM_000548.5(TSC2):c.515dup (p.Leu172fs)]

NM_000548.5(TSC2):c.515dup (p.Leu172fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000548.5(TSC2):c.515dup (p.Leu172fs)

HGVS:

NC_000016.10:g.2055435dup
NG_005895.1:g.11130dup
NM_000548.5:c.515dupMANE SELECT
NM_001077183.3:c.515dup
NM_001114382.3:c.515dup
NM_001318827.2:c.404dup
NM_001318829.2:c.368dup
NM_001318831.2:c.-1-761dup
NM_001318832.2:c.548dup
NM_001363528.2:c.515dup
NM_001370404.1:c.515dup
NM_001370405.1:c.515dup
NM_001406663.1:c.515dup
NM_001406664.1:c.515dup
NM_001406665.1:c.515dup
NM_001406667.1:c.605dup
NM_001406668.1:c.605dup
NM_001406670.1:c.404dup
NM_001406671.1:c.515dup
NM_001406673.1:c.515dup
NM_001406675.1:c.368dup
NM_001406676.1:c.368dup
NM_001406677.1:c.458dup
NM_001406678.1:c.404dup
NM_001406679.1:c.368dup
NM_001406680.1:c.-302dup
NM_001406681.1:c.53dup
NM_001406683.1:c.-302dup
NM_001406687.1:c.-302dup
NM_001406689.1:c.-917dup
NM_001406690.1:c.-917dup
NM_001406691.1:c.-917dup
NM_001406692.1:c.-917dup
NM_001406693.1:c.-1133dup
NM_001406694.1:c.-798dup
NM_001406695.1:c.-798dup
NM_001406696.1:c.-905dup
NM_001406697.1:c.-917dup
NM_001406698.1:c.-1093dup
NM_021055.3:c.515dup
NP_000539.2:p.Leu172Phefs
NP_000539.2:p.Leu172fs
NP_001070651.1:p.Leu172fs
NP_001107854.1:p.Leu172fs
NP_001305756.1:p.Leu135fs
NP_001305758.1:p.Leu123fs
NP_001305761.1:p.Leu183fs
NP_001350457.1:p.Leu172fs
NP_001357333.1:p.Leu172fs
NP_001357334.1:p.Leu172fs
NP_001393592.1:p.Leu172Phefs
NP_001393593.1:p.Leu172Phefs
NP_001393594.1:p.Leu172Phefs
NP_001393596.1:p.Leu202Phefs
NP_001393597.1:p.Leu202Phefs
NP_001393599.1:p.Leu135Phefs
NP_001393600.1:p.Leu172Phefs
NP_001393602.1:p.Leu172Phefs
NP_001393604.1:p.Leu123Phefs
NP_001393605.1:p.Leu123Phefs
NP_001393606.1:p.Leu153Phefs
NP_001393607.1:p.Leu135Phefs
NP_001393608.1:p.Leu123Phefs
NP_001393610.1:p.Leu18Phefs
NP_066399.2:p.Leu172fs
LRG_487t1:c.515dup
LRG_487:g.11130dup
LRG_487p1:p.Leu172Phefs
NC_000016.9:g.2105434_2105435insT
NC_000016.9:g.2105436dup
NM_000548.3:c.515dup
NR_176225.1:n.625dup
NR_176226.1:n.625dup
NR_176227.1:n.625dup
NR_176228.1:n.625dup
NR_176229.1:n.625dup

Protein change:

L123fs

Molecular consequence:

NM_000548.5:c.515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001077183.3:c.515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001114382.3:c.515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318827.2:c.404dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318829.2:c.368dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318832.2:c.548dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363528.2:c.515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370404.1:c.515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370405.1:c.515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406663.1:c.515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406664.1:c.515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406665.1:c.515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406667.1:c.605dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406668.1:c.605dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406670.1:c.404dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406671.1:c.515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406673.1:c.515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406675.1:c.368dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406676.1:c.368dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406677.1:c.458dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406678.1:c.404dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406679.1:c.368dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406681.1:c.53dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_021055.3:c.515dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318831.2:c.-1-761dup - intron variant - [Sequence Ontology: SO:0001627]

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
SCV003316528	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10205261, 17304050, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003316528

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 22, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Citations

PubMed

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

Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.

Au KS, Williams AT, Roach ES, Batchelor L, Sparagana SP, Delgado MR, Wheless JW, Baumgartner JE, Roa BB, Wilson CM, Smith-Knuppel TK, Cheung MY, Whittemore VH, King TM, Northrup H.

Genet Med. 2007 Feb;9(2):88-100.

PubMed [citation]

PMID:: 17304050

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV003316528.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu172Phefs*17) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050).

#	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

Last Updated: Feb 20, 2024

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