ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.416C>G (p.Ser139Cys) (rs587780732)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524494 SCV000166409 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 139 of the VHL protein (p.Ser139Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs587780732, ExAC 0.06%). This variant has not been reported in the literature in individuals with VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 135956). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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 RCV000679040 SCV000211813 uncertain significance not provided 2015-07-13 criteria provided, single submitter clinical testing This variant is denoted VHL c.416C>G at the cDNA level, p.Ser139Cys (S139C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. Although this variant has not, to our knowledge, been published in the literature as pathogenic or benign, another non-conservative amino acid substitution at this position, VHL Ser139Phe, was reported in an individual with renal cell carcinoma and other features consistent with Von Hippel Lindau disease (Hwang 2014). VHL Ser139Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. VHL Ser139Cys occurs at a position where amino acids with properties similar to Serine are tolerated across mammals and is located in the beta-domain (Yuen 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether VHL Ser139Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000123107 SCV000488489 uncertain significance Von Hippel-Lindau syndrome 2016-04-14 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679040 SCV000805348 uncertain significance not provided 2017-09-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001021981 SCV001183666 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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