ClinVar Miner

Submissions for variant NM_001354723.2(VHL):c.*31del (rs730882020)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161061 SCV000211793 pathogenic not provided 2017-10-25 criteria provided, single submitter clinical testing The c.477delA pathogenic variant in the VHL gene has been reported previously in association with von Hippel-Lindau syndrome using alternate numbering (Stolle et al., 1998). The deletion causes a frameshift starting with codon Glutamic Acid 160, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Glu160SerfsX10. This variant is predicted to cause loss of normal protein function through protein truncation as the last 54 amino acids are replaced by 9 incorrect amino acids.
Invitae RCV000687350 SCV000814913 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-03-31 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the VHL gene (p.Glu160Serfs*10). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acids of the VHL protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family affected with von Hippel-Lindau (PMID: 982991). This variant is also known as c.688delA in the literature. ClinVar contains an entry for this variant (Variation ID: 182959). A different truncation (p.Tyr175*) that lies downstream of this variant has been determined to be pathogenic (PMID: 9829912, 12202531, 15300849, Invitae). This suggests that deletion of this region of the VHL protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001406 SCV001158640 pathogenic not specified 2019-01-17 criteria provided, single submitter clinical testing The VHL c.477delA; p.Glu160fs variant (rs730882020), also reported as 688delA, is reported in the literature in a family affected with von Hippel-Lindau syndrome (Stolle 1998) and in a renal cell carcinoma sample (Taylor 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 182959). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Stolle C et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat. 1998;12(6):417-23. Taylor C et al. Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma. Int J Oncol. 2012 Oct;41(4):1229-40.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000208863 SCV000264755 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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