ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.245G>T (p.Arg82Leu) (rs794726890)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000631271 SCV000752299 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2017-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 82 of the VHL protein (p.Arg82Leu). 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 been reported to be de novo in an individual affected with bilateral adrenal pheochromocytoma (PMID: 23327821). In addition, this variant has been reported to segregate with bilateral pheochromocytoma in one family (PMID: 23626751). A different missense substitution at this codon (p.Arg82Pro) has been reported to segregate with von Hippel-Lindau syndrome in two families (PMID: 12603429, 20447124). Experimental studies have shown that this missense change disrupts the normal function of VHL protein (PMID: 26973240, 11739384, 10823831). This suggests that the arginine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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