ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.614G>A (p.Arg205His) (rs777130107)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000764460 SCV000895522 uncertain significance Erythrocytosis, familial, 2; Pheochromocytoma; Von Hippel-Lindau syndrome; Renal cell carcinoma, nonpapillary 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000481472 SCV000571135 uncertain significance not provided 2018-07-05 criteria provided, single submitter clinical testing This variant is denoted VHL c.614G>A at the cDNA level, p.Arg205His (R205H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. VHL Arg205His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within a region responsible for tumor suppression (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 Arg205His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000631259 SCV000752287 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 205 of the VHL protein (p.Arg205His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs777130107, ExAC 0.02%). This variant has not been reported in the literature in individuals with VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 421823). 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 histidine 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 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 RCV000481472 SCV000805359 uncertain significance not provided 2018-03-13 criteria provided, single submitter clinical testing

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