ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.182T>G (p.Leu61Arg) (rs118203345)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000461024 SCV000552355 likely pathogenic Tuberous sclerosis 1 2016-07-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 61 of the TSC1 protein (p.Leu61Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (rs118203345, ExAC no frequency). This variant has been reported in a family affected with tuberous sclerosis complex (TSC) (PMID: 22161988). Although it is reported to co-segregate with disease, details about the family were not provided and, therefore, it is not possible to independently assess this claim. This variant was also observed in another individual diagnosed with TSC (PMID: 22867869). Experimental studies have shown that this missense change results in reduced TSC1 protein levels, reduced inhibition of TORC1 activity, and altered intracellular expression patterns (PMID: 22161988). A different missense substitution at this codon (p.Leu61Pro) has been also observed in individuals with TSC and has been determined to be likely pathogenic (PMID: 19747374, 21309039). This suggests that the leucine residue is critical for TSC1 protein function. In summary, this variant has been shown to disrupt TSC1 protein function and it occurs at an amino acid position where a different likely pathogenic variant has been previously described. However, the available segregation evidence is limited. For these reasons, this change has been classified as Likely Pathogenic.
Tuberous sclerosis database (TSC1) RCV000054934 SCV000083149 not provided Tuberous sclerosis syndrome no assertion provided curation

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