rs118203434

Positions:

• chr9-132921367-G-A
• chr9-132921367-G-C
• chr9-132921367-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.733C>T​(p.Arg245Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC1 NM_000368.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 4.21

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 9-132921367-G-A is Pathogenic according to our data. Variant chr9-132921367-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 49091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132921367-G-A is described in Lovd as [Pathogenic]. Variant chr9-132921367-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC1	NM_000368.5	c.733C>T	p.Arg245Ter	stop_gained	8/23	ENST00000298552.9	NP_000359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC1	ENST00000298552.9	c.733C>T	p.Arg245Ter	stop_gained	8/23	1	NM_000368.5	ENSP00000298552	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 30, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change creates a premature translational stop signal (p.Arg245*) 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: 10363127, 22791573, 28968464). This variant is also known as c.954C>T. ClinVar contains an entry for this variant (Variation ID: 49091). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jul 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 20, 2024	PVS1, PS4, PM2 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 19, 2021	The TSC1 c.733C>T; p.Arg245Ter variant (rs118203434), also published as 954C>T, is reported in several individuals that met diagnostic criteria for tuberous sclerosis complex (Dabora 1998, Li 2018, Rosset). The variant is reported in the ClinVar database (Variation ID: 49091) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, loss of function is a known pathogenic mechanism in TSC1 (Northrup 2015). Based on available information, this variant is classified as pathogenic. References: Dabora SL et al. Comprehensive mutation analysis of TSC1 using two-dimensional DNA electrophoresis with DGGE. Ann Hum Genet. 1998 Nov;62(Pt 6):491-504. PMID: 10363127. Li S et al. Genotype-phenotype correlation of patients with tuberous sclerosis complex-associated renal angiomyolipoma: a descriptive study. Hum Pathol. 2018 Dec;82:61-67. PMID: 30036593. Northrup H et al. Tuberous Sclerosis Complex. 1999 Jul 13 (Updated 2015 Sep 3). In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews (Internet). Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1220/ Rosset C et al. Molecular analysis of TSC1 and TSC2 genes and phenotypic correlations in Brazilian families with tuberous sclerosis. PLoS One. 2017 Oct 2;12(10):e0185713. PMID: 28968464. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2022	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, 15798777, 17304050, 10363127, 10533066, 11112665, 15121797, 22791573, 27470532, 28065512, 30787465, 35638823, 28968464, 30036593, 31447099, 29344138) -

Tuberous sclerosis syndrome Pathogenic:1 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 19, 2018	The p.Arg245X variant in TSC1 is a well-established pathogenic variant for tuber ous sclerosis complex (TSC; Mayer 1999, Dabora 2001, Cai 2017, http://chromium.l ovd.nl/LOVD2/TSC). It has been reported by other clinical laboratories in ClinVa r (Variation ID: 49091) and was absent from large population studies. This nonse nse variant leads to a premature termination codon at position 245, which is pre dicted to lead to a truncated or absent protein. Heterozygous loss of function o f the TSC1 gene is an established disease mechanism in individuals with TSC. In summary, this variant meets criteria to be classified as pathogenic for TSC in a n autosomal dominant manner based upon predicted impact to the protein, presence in multiple affected individuals and absence in the general population. ACMG/AM P criteria applied: PVS1, PS4, PM2 (Richards (2015). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2023

The p.R245* pathogenic mutation (also known as c.733C>T), located in coding exon 6 of the TSC1 gene, results from a C to T substitution at nucleotide position 733. This changes the amino acid from an arginine to a stop codon within coding exon 6. This alteration, also referred to as 954C>T, has been observed in multiple individuals with a personal and/or family history that is consistent with TSC1-related disease (Dabora SL et al. Ann. Hum. Genet., 1998 Nov;62:491-504; Mayer K et al. Hum. Mutat., 1999;14:401-11; Au KS et al. Genet. Med., 2007 Feb;9:88-100; Jenkins D et al. Pediatr Dermatol. 2016 Sep;33(5):536-42). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.86
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs118203434; hg19: chr9-135796754; COSMIC: COSV53763655; COSMIC: COSV53763655;