ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.463+4C>T (rs879253989)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000679042 SCV000293080 uncertain significance not provided 2019-09-12 criteria provided, single submitter clinical testing In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26323595)
Invitae RCV000560865 SCV000626905 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-09-24 criteria provided, single submitter clinical testing 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 245895). 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 is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.
PreventionGenetics,PreventionGenetics RCV000679042 SCV000805350 likely benign not provided 2018-01-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV001022813 SCV001184592 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-20 criteria provided, single submitter clinical testing The c.463+4C>T intronic variant results from a C to T substitution 4 nucleotides after coding exon 2 in the VHL gene. A different nucleotide substitution at this same intronic position (c.463+4C>G) was reported in several family members from a large pedigree affected with VHL related tumors, as well as in unaffected family members (Sexton A et al. J Genet Couns, 2015 Dec;24:882-9). RNA analysis showed this alteration led to exon 2 skipping in some VHL transcripts. Given the reduced penetrance demonstrated in the pedigree, the authors speculate that normal transcript levels may be sufficient in some individuals to maintain a non-disease state. This nucleotide position is well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to weaken the efficiency of the native splice donor site, but is not predicted to have a deleterious effect on this splice donor site by ESEfinder; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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