ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.473_474delinsTT (p.Arg158Leu) (rs1567553501)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000688595 SCV000816215 pathogenic Li-Fraumeni syndrome 2018-02-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 158 of the TP53 protein (p.Arg158Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related disease. An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). A different variant (c.473G>T) giving rise to the same protein effect observed here (p.Arg158Leu) has been reported in an individual affected with adrenocortical carcinoma (PMID: 25584008), and experimental studies have shown that this variant (c.473G>T, p.Arg158Leu) disrupts TP53 protein function (PMID: 25584008, 16861262, 12725534), indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Pathogenic.

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