ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.160A>T (p.Met54Leu)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001046725 SCV001210639 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-04-17 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the VHL mRNA at codon 54 (Met54), which is responsible for translation initiation of the VHLp19 functional isoform. However, the initiator methionine at codon 1 (Met1) responsible for translation initiation of the VHLp30 functional isoform is preserved. This variant is not present in population databases (ExAC no frequency). Disruption of the initiator Met54 codon (p.Met54Ile) has been observed to be homozygous in individuals of Moroccan origin who were affected with erythrocytosis and pulmonary arterial hypertension, and reported to segregate with erythrocytosis in a family (PMID: 26224408, 27578599). However, individuals observed to be heterozygous did not present von Hippel-Lindau (VHL) associated clinical features (PMID: 26224408), suggesting that its association with VHL is currently unclear. Experimental studies using patient's cells have shown that disruption of Met54 (p.Met54Ile) affects VHLp19 expression, but does not affect VHLp30 expression (PMID: 26224408). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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