rs45451497

Positions:

• chr16-2080179-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000548.5(TSC2):​c.3412C>T​(p.Arg1138*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 4.95

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2080179-C-T is Pathogenic according to our data. Variant chr16-2080179-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 49257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2080179-C-T is described in Lovd as [Pathogenic]. Variant chr16-2080179-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3412C>T	p.Arg1138*	stop_gained	30/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3412C>T	p.Arg1138*	stop_gained	30/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 10, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This sequence change creates a premature translational stop signal (p.Arg1138*) 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 premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 10533066, 16981987). ClinVar contains an entry for this variant (Variation ID: 49257). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jul 19, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32211034, 25525159, 25782670, 15798777, 16114042, 16981987, 15121797, 10533066, 28065512, 24271014, 33807840, 31927531, 30036593, 30185235, 27535533, 11112665, 33278787) -

Tuberous sclerosis syndrome Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 05, 2017	The p.Arg1138X variant in TSC2 has been previously reported in 2 individuals with tuberous sclerosis and segregated with disease in 2 affected relatives (Mayer 1999, Cai 2017). This variant has also been reported in more than 40 sporadic TSC cases (Kwiatkowski 2015, Dabora 2001, Hung 2006, Crino 2010, Tyburczy 2014, LOVD database). Data from large population studies is insufficient to assess the frequency of this variant. The p.Arg1138X variant has been reported in ClinVar (Variation ID 49257). This nonsense variant leads to a premature termination codon at position 1138, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TSC2 gene is an established disease mechanism in tuberous sclerosis. In summary, this variant meets criteria to be classified as pathogenic for tuberous sclerosis in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1; PS4_Moderate; PP4. -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 17, 2021

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2016

The p.R1138* pathogenic mutation (also known as c.3412C>T), located in coding exon 29 of the TSC2 gene, results from a C to T substitution at nucleotide position 3412. This changes the amino acid from an arginine to a stop codon within coding exon 29. This pathogenic mutation has been reported in multiple unrelated individuals who met clinical criteria for tuberous sclerosis complex (TSC) (Mayer K et al. Hum. Mutat., 1999;14:401-11; Dabora SL et al. Am. J. Hum. Genet., 2001 Jan;68:64-80). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.97
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45451497; hg19: chr16-2130180; COSMIC: COSV54761190; COSMIC: COSV54761190;