ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.452T>C (p.Ile151Thr) (rs869025655)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492569 SCV000580978 likely pathogenic Hereditary cancer-predisposing syndrome 2016-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Integrated Genetics/Laboratory Corporation of America RCV000590238 SCV000697512 pathogenic Von Hippel-Lindau syndrome 2019-02-26 criteria provided, single submitter clinical testing Variant summary: The variant, VHL c.452T>C (p.Ile151Thr, also known as c.655T>C, p.Ile222Thr) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, alpha domain and von Hippel-Lindau disease tumour suppressor, beta/alpha domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246370 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (Hes_2007, Ong_2007, Sriphrapradang_2017, Krauss_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence assessing the variant effect on the downstream signaling mechanism of VHL but does not allow convincing conclusions about the variant effect (Walmsley_2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000705307 SCV000834297 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-04-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 151 of the VHL protein (p.Ile151Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals affected with von Hippel-Lindau (VHL) syndrome (PMID: 10567493, 28469506, 17661816, 17024664, 11309459). This variant is also known as 665T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 428803). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Different missense substitutions at this codon (p.Ile151Ser and p.Ile151Phe) have been reported in several individuals affected with VHL syndrome (PMID: 22357542, 25078357). For these reasons, this variant has been classified as Pathogenic.

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