ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.154G>A (p.Glu52Lys) (rs373068386)

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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 RCV000148923 SCV000190680 uncertain significance Von Hippel-Lindau syndrome 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Invitae RCV000227809 SCV000285488 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 52 of the VHL protein (p.Glu52Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs373068386, ExAC 0.02%). This variant has been reported in individuals affected with von Hippel-Lindau disease from one family, although it is not clear whether this variant segregates with disease in all carriers (PMID: 12202531, 15300849). These individuals are also reported in the Universal Mutation Database (UMD) (PMID: 10612827). In one of these individuals, a pathogenic allele (c.341_639del; p.Gly114fsX6) was also listed, which suggests that this c.154G>A variant was not the primary cause of disease. The presence of this pathogenic allele is not listed for other family members in UMD. ClinVar contains an entry for this variant (Variation ID: 161402). 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 lysine 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.
GeneDx RCV000236769 SCV000293309 likely benign not specified 2018-03-07 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.
Ambry Genetics RCV000575111 SCV000675792 likely benign Hereditary cancer-predisposing syndrome 2018-04-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Counsyl RCV000148923 SCV000785754 uncertain significance Von Hippel-Lindau syndrome 2017-11-20 criteria provided, single submitter clinical testing

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