ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.464-1G>A (rs5030817)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036546 SCV000060201 pathogenic Von Hippel-Lindau syndrome 2011-01-28 criteria provided, single submitter clinical testing The 464-1G>A variant has been reported in an individual with VHL syndrome (Glava c 1996). In addition, two similar variants have been reported; 464-1G>T has been reported in three individuals with VHL across three studies and 464-1G>C has be en reported in two individuals with VHL (Crossey 1994, Clinical Research Group f or VHL in Japan 1995, Kanno 1996Ong 2007). Furthermore, the 464-1G>A variant has been identified and confirmed as a somatic variant in renal cell carcinomas (va n Houwelingen 2005, Brauch 2000, Lemm 1999, Banks 2006, COSMIC). This variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the highly conserved splice consensus sequence. Therefore, this variant is h ighly likely to be pathogenic. Please note this variant has been reported in the literature as 677-1G>A as authors of older manuscripts have numbered the nucleo tides from the start of transcription rather than the start of translation of VH L.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724861 SCV000228906 pathogenic not provided 2015-05-26 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000036546 SCV000897830 pathogenic Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV001067480 SCV001232546 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-02-19 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 2) of the VHL gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruptions of this splice site have been observed in several individuals affected with von Hippel-Lindau syndrome (PMID: 8707293, 17024664, 8641976). Disruptions of this acceptor splice site are also known as variants located at c.677-1 and c.677-2 in the literature. ClinVar contains an entry for this variant (Variation ID: 43603). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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