ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs45517340
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Total submissions: 8
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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 Inc RCV000201120 SCV000255901 pathogenic Tuberous sclerosis 2 2015-08-14 criteria provided, single submitter clinical testing
Invitae RCV000201120 SCV000285400 pathogenic Tuberous sclerosis 2 2023-06-29 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49986). 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. This variant is present in population databases (rs45517340, gnomAD 0.01%). 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).
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 2018-06-12 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
Tuberous sclerosis database (TSC2) RCV000043253 SCV000067054 not provided Tuberous sclerosis syndrome no assertion provided curation

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