ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.385C>G (p.Leu129Val)

dbSNP: rs369018004
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568082 SCV000675805 likely benign Hereditary cancer-predisposing syndrome 2023-09-12 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000707457 SCV000836555 uncertain significance Chuvash polycythemia; Von Hippel-Lindau syndrome 2023-10-25 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 129 of the VHL protein (p.Leu129Val). This variant is present in population databases (rs369018004, gnomAD 0.01%). 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: 486710). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. 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.
Sema4, Sema4 RCV000568082 SCV002534169 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-23 criteria provided, single submitter curation
GeneDx RCV003441963 SCV004170319 uncertain significance not provided 2023-04-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense 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: 25885250)
Myriad Genetics, Inc. RCV004787963 SCV005407451 likely benign Von Hippel-Lindau syndrome 2024-08-16 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

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