ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1366G>A (p.Glu456Lys) (rs397515142)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000560840 SCV000644238 uncertain significance Tuberous sclerosis 2 2017-04-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 456 of the TSC2 protein (p.Glu456Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs397515142, ExAC 0.01%). This variant has been reported in individuals with tuberous sclerosis complex (TSC) in the Leiden Open-source Variation Database (PMID: 15798777, 21520333). However, in one of of these individuals a pathogenic allele was also identified in TSC1, which suggests that this c.1366G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 65190). Experimental studies have shown that this variant does not affect TSC1–TSC2 complex formation and activity in a transfection-based immunoblot assay (PMID: 21309039). In summary, this variant is a rare missense change that is not expected to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000602776 SCV000723740 likely benign not specified 2017-10-25 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Tuberous sclerosis database (TSC2) RCV000055407 SCV000083628 not provided Tuberous sclerosis syndrome no assertion provided curation

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