ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.439A>G (p.Ile147Val) (rs1057517560)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411268 SCV000488457 uncertain significance Von Hippel-Lindau syndrome 2016-04-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000455006 SCV000540658 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only reported in 1 individual; absent from ExAC
Invitae RCV000470728 SCV000553381 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-12-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 147 of the VHL protein (p.Ile147Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with bilateral kidney cancer (PMID: 20952280). ClinVar contains an entry for this variant (Variation ID: 371833). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000657081 SCV000568592 uncertain significance not provided 2017-10-19 criteria provided, single submitter clinical testing This variant is denoted VHL c.439A>G at the cDNA level, p.Ile147Val (I147V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant was observed in at least one individual with bilateral renal carcinomas (Petersson 2011). VHL Ile147Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. VHL Ile147Val occurs at a position that is not conserved and is located in the beta-domain and the region involved in binding to the CCT complex (UniProt, Yuen 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether VHL Ile147Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562695 SCV000675798 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign),Other data supporting benign classification,Other data supporting pathogenic classification
Fulgent Genetics,Fulgent Genetics RCV000764459 SCV000895521 uncertain significance Erythrocytosis, familial, 2; Pheochromocytoma; Von Hippel-Lindau syndrome; Renal cell carcinoma, nonpapillary 2018-10-31 criteria provided, single submitter clinical testing

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