ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.194C>T (p.Ser65Leu) (rs5030826)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626711 SCV000747414 pathogenic Cerebellar hemangioblastoma; Pancreatic cysts; Retinal capillary hemangioma; Spinal hemangioblastoma 2017-01-01 criteria provided, single submitter clinical testing
Invitae RCV000199197 SCV000253855 pathogenic Von Hippel-Lindau syndrome 2015-04-24 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 65 of the VHL protein (p.Ser65Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant has been reported in the literature and is not present in population databases. This variant was reported in several families of various ethnic backgrounds affected with Von Hippel-Lindau (VHL) syndrome (PMID: 7987306, 10567493, 12114495, 22799452, 25282218). This variant is also known as Ser136Leu in the literature. ClinVar contains an entry for this variant (RCV000161083). This variant falls in a mutational 'hotspot', which is defined as a clustering of plausible observations within a localized region of the protein. Other missense changes reported in suspected VHL cases include p.Ser65Trp and p.Ser65Pro, as well as several other missense variants within the same linker region of the protein. Furthermore, experimental studies have shown that missense changes in this region, including p.Ser65Leu, are deficient in promoting the degradation of the alpha subunit of the hypoxia-inducible transcription factor (PMID: 15611064). For these reasons, this variant has been classified as Pathogenic.

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