NM_000548.5(TSC2):c.3598C>T (p.Arg1200Trp) AND Tuberous sclerosis 2

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Feb 21, 2024
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:: RCV000190880.28

Allele description [Variation Report for NM_000548.5(TSC2):c.3598C>T (p.Arg1200Trp)]

NM_000548.5(TSC2):c.3598C>T (p.Arg1200Trp)

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.3598C>T (p.Arg1200Trp)

Other names:

p.R1200W:CGG>TGG

HGVS:

NC_000016.10:g.2080365C>T
NG_005895.1:g.36060C>T
NM_000548.5:c.3598C>TMANE SELECT
NM_001077183.3:c.3466C>T
NM_001114382.3:c.3598C>T
NM_001318827.2:c.3358C>T
NM_001318829.2:c.3322C>T
NM_001318831.2:c.2866C>T
NM_001318832.2:c.3499C>T
NM_001363528.2:c.3469C>T
NM_001370404.1:c.3466C>T
NM_001370405.1:c.3469C>T
NM_021055.3:c.3469C>T
NP_000539.2:p.Arg1200Trp
NP_000539.2:p.Arg1200Trp
NP_001070651.1:p.Arg1156Trp
NP_001107854.1:p.Arg1200Trp
NP_001305756.1:p.Arg1120Trp
NP_001305758.1:p.Arg1108Trp
NP_001305760.1:p.Arg956Trp
NP_001305761.1:p.Arg1167Trp
NP_001350457.1:p.Arg1157Trp
NP_001357333.1:p.Arg1156Trp
NP_001357334.1:p.Arg1157Trp
NP_066399.2:p.Arg1157Trp
LRG_487t1:c.3598C>T
LRG_487:g.36060C>T
LRG_487p1:p.Arg1200Trp
NC_000016.9:g.2130366C>T
NM_000548.3:c.3598C>T
NM_000548.4:c.3598C>T
P49815:p.Arg1200Trp
p.(Arg1200Trp)

Protein change:

R1108W

Links:

Tuberous sclerosis database (TSC2): TSC2_00056; UniProtKB: P49815#VAR_005656; dbSNP: rs45438205

NCBI 1000 Genomes Browser:

rs45438205

Molecular consequence:

NM_000548.5:c.3598C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001077183.3:c.3466C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001114382.3:c.3598C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318827.2:c.3358C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318829.2:c.3322C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318831.2:c.2866C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318832.2:c.3499C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363528.2:c.3469C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370404.1:c.3466C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370405.1:c.3469C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_021055.3:c.3469C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000245753	GeneReviews	no classification provided	not provided	germline	literature only
SCV000765896	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 8824881, 9463313, 18792920, 22867869, 25039834, 28149746, 21309039, 21332470, 28492532
SCV000782406	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001423570	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 10, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002040977	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]
SCV002768956	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21332470, 30255984, 31018109, 25741868
SCV004047668	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004930765	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Feb 21, 2024)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25039834, 32917966, 9463313, 32461669, 27406250, 21332470 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
Japanese	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel mutations detected in the TSC2 gene from both sporadic and familial TSC patients.

Wilson PJ, Ramesh V, Kristiansen A, Bove C, Jozwiak S, Kwiatkowski DJ, Short MP, Haines JL.

Hum Mol Genet. 1996 Feb;5(2):249-56.

PubMed [citation]

PMID:: 8824881

PGD on a recombinant allele: crossover between the TSC2 gene and 'linked' markers impairs accurate diagnosis.

Altarescu G, Eldar Geva T, Brooks B, Margalioth E, Levy-Lahad E, Renbaum P.

Prenat Diagn. 2008 Oct;28(10):929-33. doi: 10.1002/pd.2070.

PubMed [citation]

PMID:: 18792920

See all PubMed Citations (15)

Details of each submission

From GeneReviews, SCV000245753.2

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

#	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 Invitae, SCV000765896.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1200 of the TSC2 protein (p.Arg1200Trp). This variant is present in population databases (rs45438205, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of TSC2-related conditions (PMID: 8824881, 9463313, 18792920, 21332470, 22867869, 25039834, 28149746). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3616C>T (p.Arg1199Trp). ClinVar contains an entry for this variant (Variation ID: 49770). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21309039, 21332470). 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 Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782406.1

#	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	yes	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, SCV001423570.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Japanese	3	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		3	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002040977.1

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768956.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tuberous sclerosis-2 (MIM#613254). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical symptoms can be variable and subtle among affected individuals within the same family (PMIDs: 21332470, 31018109). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (both v2 and v3 listed 1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many unrelated individuals with tuberous sclerosis complex, and is associated with the mild phenotype (mild skin lesions, remitting epilepsy, and absence of severe ID or major organ involvement) (PMIDs: 21332470, 30255984 and ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies using HEK cells showed the variant restricted the TSC1-TSC2-dependent inhibition of TORC1 activity (PMID: 21332470). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

From Neuberg Centre For Genomic Medicine, NCGM, SCV004047668.1

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

Description

The missense variant c.3598C>T (p.Arg1200Trp) in TSC2 gene has been reported in the literature to segregate with tuberous sclerosis complex and a wide range of phenotypes including some milder cases in many families(Wentink M et.al.,2012). Experimental studies have shown that this missense change results in an unstable protein and disrupts the normal function of TSC2 as a regulator of cellular growth and proliferation(Hoogeveen-Westerveld M et.al.,2011). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg1200Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes and allele frequency of 0.003187% is reported in gnomAD. The amino acid Arg at position 1200 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties.The amino acid change p.Arg1200Trp in TSC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004930765.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21332470, 25039834, 32917966, 9463313, 32461669]. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 27406250, 21332470].

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

Last Updated: Jun 9, 2024

Relating variation to medicine