ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.331A>T (p.Ser111Cys) (rs1559426203)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000685144 SCV000812617 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-02-16 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 111 of the VHL protein (p.Ser111Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with von Hippel-Lindau syndrome (PMID: 12202531) and in individuals affected with unilateral pheochromocytoma (PMID: 12807974). Experimental studies have shown that this missense change failed to transactivate p53 upon DNA damage, due to impaired Chk2-mediated phosphorylation in vitro (PMID: 22071692). A different variant (c.543–544CA>TT) giving rise to the same protein effect observed here (p.Ser111Cys) has been reported in an individual affected with pheochromocytoma (PMID: 9829911). In addition, two different missense substitution at this codon (p.Ser111Arg and p.Ser111Asn) have been reported in individuals affected with von Hippel-Lindau syndrome (PMID: 25562111, 27527340, 14722919, 10761708, 7728151, 25867206). This suggests that the serine residue is critical for VHL protein function. For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.