ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.463+3A>C

dbSNP: rs1131690954
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001999191 SCV002284909 uncertain significance Chuvash polycythemia; Von Hippel-Lindau syndrome 2020-10-29 criteria provided, single submitter clinical testing 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. 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. This variant has been observed in individual(s) with von Hippel-Lindau syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 2 of the VHL gene. It does not directly change the encoded amino acid sequence of the VHL protein. It affects a nucleotide within the consensus splice site of the intron.
Ambry Genetics RCV002337111 SCV002635238 likely pathogenic Hereditary cancer-predisposing syndrome 2022-07-13 criteria provided, single submitter clinical testing The c.463+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 2 in the VHL gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same donor site (c.463+3A>G) has been detected in multiple individuals with VHL syndrome (Boaz RJ et al. Indian J. Endocrinol. Metab. 2011 Oct;15 Suppl 4:S402-5; Ebenazer A et al. Fam. Cancer. 2013 Sep;12(3):519-24; Ambery internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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