ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.501_502insTTGTCCGT (p.Ser168fs) (rs398123483)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723632 SCV000111080 pathogenic not provided 2014-09-25 criteria provided, single submitter clinical testing
Invitae RCV000818637 SCV000959261 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-07-11 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the VHL gene (p.Ser168Leufs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acids of the VHL protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with von Hippel-Lindau syndrome (PMID: 8493574, 7728151). This variant is also known as "8-nt insertion (714)" or "715 insTTGTCCGT" in the literature. ClinVar contains an entry for this variant (Variation ID: 93329). This variant disrupts the C-terminus of the VHL protein. Other variant(s) that disrupt this region (p.Ser183*) have been determined to be pathogenic (PMID: 8707293, 10567493, 11309459). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001023415 SCV001185285 pathogenic Hereditary cancer-predisposing syndrome 2018-02-06 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV000079210 SCV001362036 pathogenic Von Hippel-Lindau syndrome 2019-07-11 criteria provided, single submitter clinical testing Variant summary: VHL c.501_502insTTGTCCGT (p.Ser168LeufsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.525C>G, p.Tyr175X; c.548C>A, p.Ser183X; c.586A>T, p.Lys196X). The variant was absent in 251460 control chromosomes (gnomAD). The variant, c.501_502insTTGTCCGT, has been reported in the literature in one large family with several individuals affected by Von Hippel-Lindau Syndrome (Latif_1993, Chen_1995). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000079210 SCV000264766 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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