Submissions for variant NM_000368.5(TSC1):c.733C>T (p.Arg245Ter)

dbSNP: rs118203434

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000201189	SCV000255865	pathogenic	Tuberous sclerosis 1	2014-05-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000255397	SCV000322135	pathogenic	not provided	2022-06-22	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV000491872	SCV000579949	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-02	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201189	SCV000763648	pathogenic	Tuberous sclerosis 1	2025-01-08	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000042345	SCV000966990	pathogenic	Tuberous sclerosis syndrome	2018-01-19	criteria provided, single submitter	clinical testing	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).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000201189	SCV001428656	likely pathogenic	Tuberous sclerosis 1	2019-04-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000201189	SCV002039544	pathogenic	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255397	SCV002049048	pathogenic	not provided	2021-05-19	criteria provided, single submitter	clinical testing	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.
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000201189	SCV002549096	pathogenic	Tuberous sclerosis 1	2022-07-17	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000201189	SCV002581245	pathogenic	Tuberous sclerosis 1	2021-10-19	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000201189	SCV005043862	pathogenic	Tuberous sclerosis 1	2024-02-20	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000201189	SCV005416347	pathogenic	Tuberous sclerosis 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4_Moderate+PP4
Neuberg Centre For Genomic Medicine, NCGM	RCV000201189	SCV005442692	pathogenic	Tuberous sclerosis 1		criteria provided, single submitter	clinical testing	The observed stop gain c.733C>T p.Arg245Ter variant in TSC1 gene has been previously reported in heterozygous state in multiple individuals affected with Tuberous sclerosis Craiu DC et al. 2022; Wang W et al. 2022. The p.Arg245Ter variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic/ Pathogenic multiple submitters. The reference nucleotide change c.733C>T on TSC1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in TSC1 are known to be pathogenic Au KS et al. 2007. For these reasons, this variant has been classified as Pathogenic.
Tuberous sclerosis database (TSC1)	RCV000042345	SCV000066134	not provided	Tuberous sclerosis syndrome		no assertion provided	curation