ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.2477T>C (p.Leu826Pro) (rs45517239)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000473440 SCV000544517 likely pathogenic Tuberous sclerosis 2 2016-04-14 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 826 of the TSC2 protein (p.Leu826Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with suspected tuberous sclerosis complex (PMID: 22903760), and in affected individuals in the Leiden Open-source Variation Database (PMID: 21520333), including an affected individual in which this variant was reported to arise de novo. ClinVar contains an entry for this variant (Variation ID: 49751). An experimental study in vitro has shown that this missense change results in both reduced TSC2 and TSC1 protein levels, suggesting that the stable TSC1-TSC2 (hamartin-tuberin) complex is disrupted, and impairs the ability of this complex to inhibit TORC1 kinase (PMID: 22903760). In summary, this rare missense variant has been shown to compromise protein function and has been reported in affected individuals, including a de novo case. In the absence of segregation or additional functional data, this variant has been classified as Likely Pathogenic.
Tuberous sclerosis database (TSC2) RCV000043016 SCV000066814 not provided Tuberous sclerosis syndrome no assertion provided curation

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