ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.556G>A (p.Glu186Lys) (rs367545984)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148924 SCV000190681 uncertain significance Von Hippel-Lindau syndrome 2014-06-01 no assertion criteria provided research
GeneDx RCV000589801 SCV000292944 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted VHL c.556G>A at the cDNA level, p.Glu186Lys (E186K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Using alternate nomenclature, this variant would be defined as VHL c.769G>A or p.E257K. This variant was observed in an individual who was diagnosed with renal cell carcinoma and reported in a VHL family (Chen 1995, Zbar 1996, Neumann 1998, Gallou 1999). VHL Glu186Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the alpha domain and the elongin C binding domain (Yuen 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether VHL Glu186Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589801 SCV000697526 uncertain significance not provided 2016-02-04 criteria provided, single submitter clinical testing Variant summary: Variant affects a conserved nucleotide and result in replacement of a medium size and acidic Glutamic acid (E) with a large size and basic Lysine (K). 3/4 in silico tools predict the variant to be disease causing. It was observed in the Non-Finnish European subcohort of the ExAC project at an allele frequency of 0.003% which exceeds the maximal expected allele frequency of a disease causing VHL variant (0.002). However, the variant was identified in only 2 individuals; therefore the significance of these observations is uncertain. The variant was reported in a Korean family in which the variant carriers presented with Angioma, hemangioblastoma of the brain and renal cell carcinoma (Chen_HumMutat_1995). Additional patients with Type I disease were also reported to carry the variants, however these reports lack information about the prevalence of the variant in healthy individuals, therefore association between the variant and the disease remains uncertain (Stolle_HumMutat_1998, Hwang_JHG_2014, Zbar_HumMutat_1996). HGMD lists variant affecting the same codon c.556G>G (p.E186X) and variants in the close proximity of the variant of interest c.555C>A and c.555C>G (p.Y185X) indicating the variant to be located in a mutational hotspot and suggesting pathogenicity. However, a clinical laboratory classify variant as Uncertain via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant is classified as VUS-possibly pathogenic until more information becomes available.
Invitae RCV000698671 SCV000827351 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-09-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 186 of the VHL protein (p.Glu186Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs367545984, ExAC 0.003%). This variant has been reported in a family affected with von Hippel-Lindau syndrome (PMID: 7728151). ClinVar contains an entry for this variant (Variation ID: 161403). This variant is also known as 769G>T(p.Glu186Lys). 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. 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.
PreventionGenetics RCV000589801 SCV000805357 uncertain significance not provided 2017-08-23 criteria provided, single submitter clinical testing

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