ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.631A>C (p.Met211Leu) (rs200019083)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161101 SCV000211836 likely benign not specified 2016-12-06 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000287076 SCV000439637 likely benign Von Hippel-Lindau syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000161101 SCV000697528 uncertain significance not specified 2018-05-15 criteria provided, single submitter clinical testing Variant summary: VHL c.631A>C (p.Met211Leu) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 276540 control chromosomes (gnomAD). The observed variant frequency is approximately 1.2 fold above the estimated maximal expected allele frequency for a pathogenic variant in VHL causing Von Hippel-Lindau Syndrome phenotype (2.1e-05), suggesting that the variant might be benign. The variant, c.631A>C, has been reported in the literature in individuals affected with Breast Cancer (Jalkh_2017). This report does not provide unequivocal conclusions about association of the variant with Von Hippel-Lindau Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x likely benign, 1x uncertain significance). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000541199 SCV000626914 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 211 of the VHL protein (p.Met211Leu). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs200019083, ExAC 0.03%). This variant has been reported in an individual with breast cancer (PMID: 28202063). ClinVar contains an entry for this variant (Variation ID: 182990). 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 leucine 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.

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