ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.1A>T (p.Met1Leu)

gnomAD frequency: 0.00001  dbSNP: rs1060503557
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000458939 SCV000553394 uncertain significance Chuvash polycythemia; Von Hippel-Lindau syndrome 2024-01-10 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the VHL mRNA. The next in-frame methionine is located at codon 54. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 54 has the potential to rescue this variant. This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 411967). Several studies have shown that the VHL protein created from a downstream methionine located at codon 54 is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722). 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.
GeneDx RCV000579235 SCV000680941 uncertain significance not provided 2024-02-12 criteria provided, single submitter clinical testing Initiation codon variant in a gene for which a downstream in-frame ATG produces an alternate clinically-relevant isoform, pVHL19, that may result in a functional protein (PMID: 9751722, 10102622, 9671762); Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9751722, 10102622, 26211615, 23541568, 9671762)
Counsyl RCV000663055 SCV000786106 uncertain significance Von Hippel-Lindau syndrome 2018-03-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV002418424 SCV002721817 likely benign Hereditary cancer-predisposing syndrome 2021-10-14 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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