rs118203542

Positions:

• chr9-132906053-G-A
• chr9-132906053-G-C
• chr9-132906053-G-T

Variant summary

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

The NM_000368.5(TSC1):​c.1525C>T​(p.Arg509Ter) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R509R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:2
• Conservation: PhyloP100: 3.26

Genes affected

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. 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 9-132906053-G-A is Pathogenic according to our data. Variant chr9-132906053-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 48796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132906053-G-A is described in Lovd as [Pathogenic]. Variant chr9-132906053-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.1525C>T	p.Arg509Ter	stop_gained	15/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.1525C>T	p.Arg509Ter	stop_gained	15/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Pathogenic:6

Likely pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_000368.5:c.1525C>T (chr9:132906053) in TSC1 was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PM2, PP5_Strong) this variant classifies as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Apr 07, 2022	ACMG categories: PVS1,PS2,PM2,PP3,PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jun 09, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000048796 / PMID: 9242607). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change creates a premature translational stop signal (p.Arg509*) in the TSC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 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: 9242607, 9863590, 9924605, 11112665, 16981987, 20547222, 21520333, 25900779). This variant is also known as 1746C>T. ClinVar contains an entry for this variant (Variation ID: 48796). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 20, 2021	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2022	Published functional studies demonstrate that R509X prevents TSC1 aggregation (Hoogeveen-Westerveld et al., 2010); Mosaic variant in a patient with TSC previously tested at GeneDx; 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 (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 29642139, 29932062, 20547222, 9328481, 10533066, 11112665, 9924605, 25900779, 9242607, 28288225, 34426522, 29655203, 32211034, 32655475, 34403804, 34849272, 33826429, 28087349) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 06, 2021	PVS1, PS4, PM2, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 20, 2021	The TSC1 c.1525C>T (p.Arg509*) variant has been reported in the published literature in affected individuals with tuberous scelorosis complex (PMIDs: 9242607 (1997), 9328481 (1997), 9863590 (1998), 9924605 (1998), 16981987 (2006), 25900779 (2015), 32211034 (2020), 34403804 (2021), and 35918040 (2022)). It has also been reported in patients with epilepsy (PMIDs: 29655203 (2018) and 32655475 (2020)). A functional study demonstrated that this variant is damaging to protein function (PMID: 20547222 (2010)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Oct 10, 2022	TSC1 NM_000368.4 exon 15 p.Arg509* (c.1525C>T): This variant has been reported in the literature in several individuals with tuberous sclerosis (Ali 1998 PMID:9863590, Kwiatkowska 1998 PMID:9924605, Dabora 2001 PMID:11112665, Hung 2006 PMID:16981987, Hoogeveen-Westerveld 2010 PMID:20547222, Zhang 2015 PMID:25900779), including multiple entries in the Tuberous Sclerosis Database (http://chromium.lovd.nl/LOVD2/TSC/variants), with several of these entries reported to be de novo. This variant is not present in large control databases, but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:48796). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In vitro functional studies predict that this variant will impact the protein by impairing TSC1 aggregation (Hoogeveen-Westerveld 2010 PMID:20547222). However, these studies may not accurately represent in vivo biological function. 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 based on the data above. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2021

The p.R509* pathogenic mutation (also known as c.1525C>T), located in coding exon 13 of the TSC1 gene, results from a C to T substitution at nucleotide position 1525. This changes the amino acid from an arginine to a stop codon within coding exon 13. The alteration has been reported in multiple individuals who met diagnostic criteria for tuberous sclerosis complex (TSC)(van Slegtenhorst M et al. Science, 1997 Aug;277:805-8; Zhang H et al. J. Hum. Genet., 1999;44:391-6; Zhang Y et al. Neuromolecular Med., 2015 Jun;17:202-8). 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 (TSC1)

-

- -

Malignant tumor of urinary bladder Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC1)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A;A;D
Vest4		0.78
GERP RS		5.1
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: rs118203542; hg19: chr9-135781440; COSMIC: COSV53764587; COSMIC: COSV53764587;