ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.345C>A (p.His115Gln) (rs864622646)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588324 SCV000697502 pathogenic Von Hippel-Lindau syndrome 2016-02-05 criteria provided, single submitter clinical testing Variant summary: This c.345C>A affects a non-conserved nucleotide, resulting in amino acid change from His to Gln. 2/3 in-silico tools predict this variant to be damaging. The residue p.His115 is reported to be critical for interaction with HIF, thus this missense change is unlikely to be tolerated. By a structural/functional assay, interaction energy of residue was ~1.5 kcal/mol weaker than that with histidine in the wild type (Domene_2012), thus proving that the variant leads to functional impairment. This variant was not found in approximately 121600 control chromosomes, including the broad and large populations from ExAC. In literature, the p.His115Gln has been reported as a pathogenic variant found in >6 independent VHL patients/families, including somatic occurrences. At least one database calls this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic.
Invitae RCV001044333 SCV001208124 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-03-19 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 115 of the VHL protein (p.His115Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with Von Hippel-Lindau syndrome (VHL) or clinical features of VHL (PMID: 19949673, 9829912, 7728151, 9681856, 29749453). ClinVar contains an entry for this variant (Variation ID: 496057). This variant has been reported to affect VHL protein function (PMID:28775317). This variant disrupts the p.His115 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 17024664, 8707293, 22357542), which suggests that this may be a clinically significant amino acid residue. 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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