ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.733C>T (p.Arg245Ter) (rs118203434)

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Total submissions: 6
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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 2017-11-16 criteria provided, single submitter clinical testing The R245X nonsense variant in the TSC1 gene has been reported multiple times previously inassociation with TSC (Dabora et al., 1998; Au et al., 2007; TSC1 LOVD). This pathogenic variant ispredicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R245X variant is not observed in large population cohorts (Lek et al.,2016). Therefore, the presence of R245X is consistent with the diagnosis of TSC in this individual.
Ambry Genetics RCV000491872 SCV000579949 pathogenic Hereditary cancer-predisposing syndrome 2017-09-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000201189 SCV000763648 pathogenic Tuberous sclerosis 1 2018-11-01 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).
Tuberous sclerosis database (TSC1) RCV000042345 SCV000066134 not provided Tuberous sclerosis syndrome no assertion provided curation

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