ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.154G>A (p.Glu52Lys)

dbSNP: rs373068386
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington 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 likely benign Chuvash polycythemia; Von Hippel-Lindau syndrome 2024-01-31 criteria provided, single submitter clinical testing
GeneDx RCV001704076 SCV000293309 likely benign not provided 2021-03-05 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 11257211, 25637381, 27651169, 26211615, 9829912, 24138046, 12202531, 24055113, 21463266, 15300849, 18836774, 19574279, 18416845)
Ambry Genetics RCV000575111 SCV000675792 likely benign Hereditary cancer-predisposing syndrome 2018-04-26 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl RCV000148923 SCV000785754 uncertain significance Von Hippel-Lindau syndrome 2017-11-20 criteria provided, single submitter clinical testing
Mendelics RCV000148923 SCV001136309 benign Von Hippel-Lindau syndrome 2023-08-22 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000575111 SCV002534143 likely benign Hereditary cancer-predisposing syndrome 2021-06-18 criteria provided, single submitter curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000148923 SCV002584740 uncertain significance Von Hippel-Lindau syndrome 2022-06-20 criteria provided, single submitter clinical testing The VHL c.154G>A (p.Glu52Lys) missense change has a maximum subpopulation frequency of 0.075% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with Von Hippel-Lindau disease (PMID: 12202531). In summary, the evidence currently available is insufficient to determine the role of this variant in disease. It has therefore been classified as of uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002465537 SCV002760267 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001704076 SCV003820403 uncertain significance not provided 2022-09-22 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003415985 SCV004116597 uncertain significance VHL-related disorder 2022-12-22 criteria provided, single submitter clinical testing The VHL c.154G>A variant is predicted to result in the amino acid substitution p.Glu52Lys. This variant has been reported in patients with von Hippel-Lindau disease with and without renal involvement (Dollfus et al. 2002. PubMed ID: 12202531; Supplementary Table S1, Gallou et al. 2004. PubMed ID: 15300849). In addition, this variant has been identified and classified as a variant of uncertain significant in a study analyzing incidental findings in patients of European and African-ancestry that participated in the National Heart, Lung, and Blood Institute Exome Sequencing Project (Supplementary Table 1, Amendola et al. 2015. PubMed ID: 25637381; Supplementary Table 1, Dorschner et al. 2013. PubMed ID: 24055113). This variant has also been reported in an individual with hepatoblastoma (Aguiar et al. 2022. PubMed ID: 35495172). However, this variant is reported in 0.075% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-10183685-G-A), which may be too common to be a primary cause of disease. This variant has interpretations of likely benign, uncertain, and likely pathogenic in ClinVar (ncbi.nlm.nih.gov/clinvar/variation/161402) Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen RCV001704076 SCV004146915 uncertain significance not provided 2023-06-01 criteria provided, single submitter clinical testing VHL: PS4:Moderate
Color Diagnostics, LLC DBA Color Health RCV000148923 SCV004360952 uncertain significance Von Hippel-Lindau syndrome 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 52 of the VHL protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in families and individuals affected with Von Hippel-Lindau disease (PMID: 12202531, 15300849). This variant has been identified in 19/222880 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Molecular Oncology - Human Genetics Lab, University of Sao Paulo RCV001843484 SCV002103100 likely pathogenic Hepatoblastoma flagged submission research
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine RCV002467589 SCV002764242 likely pathogenic Enchondromatosis flagged submission research

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