16-2064341-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.1513C>T(p.Arg505Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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:12 O:2
• Conservation: PhyloP100: 3.24

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]

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 16-2064341-C-T is Pathogenic according to our data. Variant chr16-2064341-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2064341-C-T is described in Lovd as [Pathogenic]. Variant chr16-2064341-C-T is described in Lovd as [Likely_pathogenic]. Variant chr16-2064341-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.1513C>T	p.Arg505Ter	stop_gained	15/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.1513C>T	p.Arg505Ter	stop_gained	15/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 10, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 8824881, 28968464, 25525159] -
Pathogenic, no assertion criteria provided	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jun 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_000548.5:c.1513C>T (chr16:2064341) in TSC2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 20, 2023	This sequence change creates a premature translational stop signal (p.Arg505*) 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: 8824881, 9463313, 10205261, 11112665, 16114042, 16981987). ClinVar contains an entry for this variant (Variation ID: 12396). For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 23, 2021	TSC2 NM_000548 exon 15 p.Arg505* (c.1513C>T): This variant has been reported in the literature in at least 10 individuals with Tuberous sclerosis (Wilson 1996 PMID:8824881, Jones 1999 PMID:10205261, Mayer 1999 PMID:10533066, Dabora 2001 PMID:11112665, Rendtorff 2005 PMID:16114042, Hung 2006 PMID:16981987, Au 2007 PMID:17304050). This variant is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Rosset 2017 PMID:28222202). In summary, this variant is classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TSC2: PVS1, PM2, PS4:Moderate, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2017

The p.R505* pathogenic mutation (also known as c.1513C>T), located in coding exon 14 of the TSC2 gene, results from a C to T substitution at nucleotide position 1513. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration has been reported in multiple individuals meeting diagnostic criteria for tuberous sclerosis complex (TSC) (Rendtorff ND et al. Hum. Mutat., 2005 Oct;26:374-83; Wilson PJ et al. Hum. Mol. Genet., 1996 Feb;5:249-56; Hung CC et al. BMC Med. Genet., 2006 Sep;7:72). 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. -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

-

- -

Lymphangiomyomatosis Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.95
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs45517179; hg19: chr16-2114342; COSMIC: COSV54756671; COSMIC: COSV54756671;