NM_000548.5(TSC2):c.2647C>T (p.Gln883Ter) AND Tuberous sclerosis 2

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Mar 2, 2021
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:: RCV001252981.7

Allele description [Variation Report for NM_000548.5(TSC2):c.2647C>T (p.Gln883Ter)]

NM_000548.5(TSC2):c.2647C>T (p.Gln883Ter)

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.2647C>T (p.Gln883Ter)

HGVS:

NC_000016.10:g.2076075C>T
NG_005895.1:g.31770C>T
NM_000548.5:c.2647C>TMANE SELECT
NM_001077183.3:c.2647C>T
NM_001114382.3:c.2647C>T
NM_001318827.2:c.2536C>T
NM_001318829.2:c.2500C>T
NM_001318831.2:c.2047C>T
NM_001318832.2:c.2680C>T
NM_001363528.2:c.2647C>T
NM_001370404.1:c.2647C>T
NM_001370405.1:c.2647C>T
NM_021055.3:c.2647C>T
NP_000539.2:p.Gln883Ter
NP_001070651.1:p.Gln883Ter
NP_001107854.1:p.Gln883Ter
NP_001305756.1:p.Gln846Ter
NP_001305758.1:p.Gln834Ter
NP_001305760.1:p.Gln683Ter
NP_001305761.1:p.Gln894Ter
NP_001350457.1:p.Gln883Ter
NP_001357333.1:p.Gln883Ter
NP_001357334.1:p.Gln883Ter
NP_066399.2:p.Gln883Ter
LRG_487t1:c.2647C>T
LRG_487:g.31770C>T
NC_000016.9:g.2126076C>T
NM_000548.3:c.2647C>T
NM_000548.4:c.2647C>T
p.(Gln883*)

Protein change:

Q683*

Links:

Tuberous sclerosis database (TSC2): TSC2_00913; dbSNP: rs45476100

NCBI 1000 Genomes Browser:

rs45476100

Molecular consequence:

NM_000548.5:c.2647C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001077183.3:c.2647C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001114382.3:c.2647C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001318827.2:c.2536C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001318829.2:c.2500C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001318831.2:c.2047C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001318832.2:c.2680C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001363528.2:c.2647C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001370404.1:c.2647C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001370405.1:c.2647C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_021055.3:c.2647C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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
SCV001428468	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002241301	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 2, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26540169, 10205261, 17304050, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001428468

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 22, 2019)

germline

clinical testing

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

SCV002241301

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 2, 2021)

germline

clinical testing

PubMed (4)
[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	yes	1	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing.

Tyburczy ME, Dies KA, Glass J, Camposano S, Chekaluk Y, Thorner AR, Lin L, Krueger D, Franz DN, Thiele EA, Sahin M, Kwiatkowski DJ.

PLoS Genet. 2015 Nov;11(11):e1005637. doi: 10.1371/journal.pgen.1005637.

PubMed [citation]

PMID:: 26540169
PMCID:: PMC4634999

See all PubMed Citations (5)

Details of each submission

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001428468.1

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002241301.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 26540169). ClinVar contains an entry for this variant (Variation ID: 49580). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln883*) 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: Sep 29, 2024

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