ClinVar Miner

Submissions for variant NM_000368.5(TSC1):c.733C>T (p.Arg245Ter) (rs118203434)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201189 SCV000255865 pathogenic Tuberous sclerosis 1 2014-05-30 criteria provided, single submitter clinical testing
GeneDx RCV000255397 SCV000322135 pathogenic not provided 2019-10-25 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31447099, 28065512, 27470532, 22791573, 15121797, 11112665, 10533066, 30036593, 28968464, 10363127, 17304050, 25525159, 15798777)
Ambry Genetics RCV000491872 SCV000579949 pathogenic Hereditary cancer-predisposing syndrome 2017-09-27 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 mutation (also referred to as 954C>T) has been reported in multiple patients with tuberous sclerosis complex (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). 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.
Invitae RCV000201189 SCV000763648 pathogenic Tuberous sclerosis 1 2020-10-13 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. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in in individuals affected with tuberous sclerosis complex (PMID: 10363127, 22791573, 28968464). This variant is also known as c.954C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 49091). Loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 17304050). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare 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 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
Tuberous sclerosis database (TSC1) RCV000042345 SCV000066134 not provided Tuberous sclerosis syndrome no assertion provided curation

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