NM_000548.5(TSC2):c.3791del (p.Pro1264fs) AND Tuberous sclerosis 2

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 13, 2023
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:: RCV000702623.8

Allele description [Variation Report for NM_000548.5(TSC2):c.3791del (p.Pro1264fs)]

NM_000548.5(TSC2):c.3791del (p.Pro1264fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000548.5(TSC2):c.3791del (p.Pro1264fs)

HGVS:

NC_000016.10:g.2081775del
NC_000016.9:g.2131772del
NG_005895.1:g.37470del
NM_000548.5:c.3791delMANE SELECT
NM_001077183.3:c.3659del
NM_001114382.3:c.3791del
NM_001318827.2:c.3551del
NM_001318829.2:c.3515del
NM_001318831.2:c.3059del
NM_001318832.2:c.3692del
NM_001363528.2:c.3662del
NM_001370404.1:c.3659del
NM_001370405.1:c.3662del
NM_021055.3:c.3662del
NP_000539.2:p.Pro1264fs
NP_001070651.1:p.Pro1220fs
NP_001107854.1:p.Pro1264fs
NP_001305756.1:p.Pro1184fs
NP_001305758.1:p.Pro1172fs
NP_001305760.1:p.Pro1020fs
NP_001305761.1:p.Pro1231fs
NP_001350457.1:p.Pro1221fs
NP_001357333.1:p.Pro1220fs
NP_001357334.1:p.Pro1221fs
NP_066399.2:p.Pro1221fs
LRG_487t1:c.3791del
LRG_487:g.37470del
NC_000016.9:g.2131772del
NC_000016.9:g.2131772delC
NC_000016.9:g.2131776del
NM_000548.3:c.3791delC
p.Pro1264Leufs*61
p.(Pro1264Leufs*61)

Protein change:

P1020fs

Links:

Tuberous sclerosis database (TSC2): TSC2_00534; dbSNP: rs137854001

NCBI 1000 Genomes Browser:

rs137854001

Molecular consequence:

NM_000548.5:c.3791del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001077183.3:c.3659del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001114382.3:c.3791del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318827.2:c.3551del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318829.2:c.3515del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318831.2:c.3059del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001318832.2:c.3692del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363528.2:c.3662del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370404.1:c.3659del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001370405.1:c.3662del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_021055.3:c.3662del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

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

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F0F1 ATP synthase subunit A [Paenibacillus thiaminolyticus]
F0F1 ATP synthase subunit A [Paenibacillus thiaminolyticus]
gi|2436995249|gnl|PRJNA847012|NDS46 0|gb|WCF07992.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000831483	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10205261, 17304050, 28492532
SCV002040984	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002549085	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2022)	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

SCV000831483

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 13, 2023)

germline

clinical testing

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

SCV002040984

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 7, 2021)

germline

clinical testing

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

SCV002549085

Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 17, 2022)

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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
Japanese	germline	yes	1	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, SCV000831483.4

#	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. ClinVar contains an entry for this variant (Variation ID: 49568). 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.Pro1264Leufs*61) 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

From Genome-Nilou Lab, SCV002040984.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, SCV002549085.1

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

#	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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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