ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.393C>A (p.Asn131Lys)

dbSNP: rs1064794272
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482784 SCV000568591 likely pathogenic not provided 2020-10-26 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22105611, 15300849, 18836774, 9829912, 17661816, 24166983, 20660572, 17696210, 20151405, 19238077, 21384277, 29748190)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000482784 SCV000697510 uncertain significance not provided 2016-02-09 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002525827 SCV003525092 pathogenic Chuvash polycythemia; Von Hippel-Lindau syndrome 2022-02-05 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn131 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10761708, 17001110, 21384277, 27527340; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 420074). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 9829912, 15300849, 21384277). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 131 of the VHL protein (p.Asn131Lys).

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