ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.340+677G>A

dbSNP: rs2125125965
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002037254 SCV002114059 uncertain significance Chuvash polycythemia; Von Hippel-Lindau syndrome 2023-09-27 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the VHL gene. It is not expected to change the encoded amino acid sequence of the VHL protein. However, this sequence change falls within a cryptic exon in the VHL gene, known as exon E1’, which is naturally expressed at low levels in several human tissues (PMID: 29891534). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 1345390). Experimental studies have shown that this variant disrupts the relative levels of naturally occurring VHL mRNA isoforms, increasing expression of exon E1’ containing isoforms and decreasing the expression of the major mRNA isoforms of VHL which do not contain exon E1’ (PMID: 29891534, 31350093, 31996412). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.

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