NM_000548.5(TSC2):c.4351dup (p.Arg1451fs) AND Tuberous sclerosis 2

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 11, 2022
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:: RCV000817575.6

Allele description [Variation Report for NM_000548.5(TSC2):c.4351dup (p.Arg1451fs)]

NM_000548.5(TSC2):c.4351dup (p.Arg1451fs)

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.4351dup (p.Arg1451fs)

HGVS:

NC_000016.10:g.2084573dup
NG_005895.1:g.40268dup
NM_000548.4:c.4351dupC
NM_000548.5:c.4351dupMANE SELECT
NM_001077183.3:c.4150dup
NM_001114382.3:c.4282dup
NM_001318827.2:c.4042dup
NM_001318829.2:c.4006dup
NM_001318831.2:c.3619dup
NM_001318832.2:c.4183dup
NM_001363528.2:c.4153dup
NM_001370404.1:c.4219dup
NM_001370405.1:c.4222dup
NM_021055.3:c.4222dup
NP_000539.2:p.Arg1451fs
NP_001070651.1:p.Arg1384fs
NP_001107854.1:p.Arg1428fs
NP_001305756.1:p.Arg1348fs
NP_001305758.1:p.Arg1336fs
NP_001305760.1:p.Arg1207fs
NP_001305761.1:p.Arg1395fs
NP_001350457.1:p.Arg1385fs
NP_001357333.1:p.Arg1407fs
NP_001357334.1:p.Arg1408fs
NP_066399.2:p.Arg1408fs
LRG_487t1:c.4351dup
LRG_487:g.40268dup
NC_000016.9:g.2134568_2134569insC
NC_000016.9:g.2134574dup
NM_000548.3:c.4351dupC
p.(Arg1451Profs*73)

Protein change:

R1207fs

Links:

Tuberous sclerosis database (TSC2): TSC2_01172; dbSNP: rs397514939

NCBI 1000 Genomes Browser:

rs397514939

Molecular consequence:

NM_000548.5:c.4351dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001077183.3:c.4150dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001114382.3:c.4282dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318827.2:c.4042dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318829.2:c.4006dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318831.2:c.3619dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318832.2:c.4183dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363528.2:c.4153dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370404.1:c.4219dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370405.1:c.4222dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_021055.3:c.4222dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000958144	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 11, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10205261, 17304050, 28492532
SCV004100452	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	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

SCV000958144

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 11, 2022)

germline

clinical testing

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

SCV004100452

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

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	germline	yes	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 (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000958144.3

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

Description

This sequence change creates a premature translational stop signal (p.Arg1451Profs*73) 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). 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: 65040). 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 Neuberg Centre For Genomic Medicine, NCGM, SCV004100452.1

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

Description

The frameshift duplication p.R1451Pfs*73 in TSC2 (NM_000548.5) has been reported in ClinVar as Pathogenic. The p.R1451Pfs*73 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. The frame shifted sequence continues 73 residues until a stop codon is reached. For these reasons, this variant has been classified as Likely Pathogenic.

#	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: Sep 29, 2024

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