Submissions for variant NM_000548.5(TSC2):c.4375C>T (p.Arg1459Ter)

gnomAD frequency: 0.00003  dbSNP: rs45517340

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000190004	SCV000243676	pathogenic	not provided	2022-01-21	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; This variant is associated with the following publications: (PMID: 17304050, 26408672, 10570911, 10533067, 28968464, 20633017, 10205261, 25525159, 18978035, 14508401, 25782670, 28830860, 31856217, 31291687, 33278787, 32005694, 27535533, 32313033, 33294277)
Athena Diagnostics	RCV000201120	SCV000255901	pathogenic	Tuberous sclerosis 2	2015-08-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201120	SCV000285400	pathogenic	Tuberous sclerosis 2	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1459*) 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 present in population databases (rs45517340, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 10205261, 10533067, 10570911, 11112665, 14508401, 20633017, 28968464). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49986). 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.
Genome-Nilou Lab	RCV000201120	SCV002040994	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000201120	SCV002512256	pathogenic	Tuberous sclerosis 2	2022-01-13	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PM6 moderate, PP1 supporting
Ambry Genetics	RCV002326764	SCV002631142	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-07	criteria provided, single submitter	clinical testing	The p.R1459* pathogenic mutation (also known as c.4375C>T), located in coding exon 33 of the TSC2 gene, results from a C to T substitution at nucleotide position 4375. This changes the amino acid from an arginine to a stop codon within coding exon 33. This mutation has been detected in several unrelated individuals of various ethnic backgrounds reported to have diagnosed or suspected tuberous sclerosis complex (Jones AC et al. Am J Hum Genet. 1999;64:1305-15; Niida Y et al. Hum Mutat. 1999;14:412-22; Zhang H et al. J Hum Genet. 1999;44:391-6; Dabora SL et al. Am J Hum Genet. 2001;68:64-80; Breathnach C et al. Pediatrics. 2014;134:e1199-202; Bai D et al. Sci China Life Sci. 2017;60:763-771; Rosset C et al. PLoS ONE. 2017;12:e0185713). 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.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000201120	SCV004123043	pathogenic	Tuberous sclerosis 2	2023-07-01	criteria provided, single submitter	research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000043253	SCV005201012	pathogenic	Tuberous sclerosis syndrome	2024-09-05	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC2)	RCV000043253	SCV000067054	not provided	Tuberous sclerosis syndrome		no assertion provided	curation