ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.491A>G (p.Gln164Arg) (rs267607170)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000002326 SCV000697523 pathogenic Von Hippel-Lindau syndrome 2016-02-04 criteria provided, single submitter clinical testing Variant summary: This VHL c.491A>G variant affects a conserved nucleotide, resulting in amino acid change from Gln to Arg in the alpha domain of the VHL protein, a residue that resides on the surface of the protein. Missense mutations at VHL protein surface residues that do not cause a total loss of function are associated with a high risk of pheochromocytoma (Type 2A, 2B, and 2C phenotypes) [Crossey et al., 1994; Chen et al., 1995; Zbar et al., 1996; Maher, 2004, 2006]. 2/3 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index; SIFT has no prediction). The variant significantly reduced binding to elongin B, elongin C, and Cul2 in one functional study (Ohh_1999); however, another functional assay showed no effect on binding (Park_2015). The latter study found that this variant significantly reduced the stability of VHL protein, which is implicated for its pathogenicity. Neither of these reports provided input control blots for these interaction assays, thus the conflicting binding results may be explained by overexpression artifacts.This variant was not found in approximately 121306 control chromosomes including the broad and large populations from ExAC. However, this variant has been reported in at least five independent VHL patients/families or patients with VHL-related cancers, including one patient who carried this variant as a somatic occurrence. Published evidence suggests that patients with this variant will likely have VHL disease primarily manifested by pheochromocytoma. One reported family had this variant in a father and son, both affected by pheochromocytoma. The father had this variant de novo, strongly suggesting for a pathogenic outcome (Sovinz _2010). Additionally, other likely pathogenic variants (p.Q164H, p.Q164*, etc.) have also been reported at this p.C164 residue, suggesting that this codon could be a mutational hot-spot. Taken together, this is a disease variant and has been classified as pathogenic.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000002326 SCV000897835 pathogenic Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001023261 SCV001185112 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-22 criteria provided, single submitter clinical testing Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV001052383 SCV001216592 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2020-01-01 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 164 of the VHL protein (p.Gln164Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with von Hippel-Lindau disease (PMID: 7728151, 20583150, 17024664). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 2238). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Gln164 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24102379, 22517557, 19215943, 12807974, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002326 SCV000022484 pathogenic Von Hippel-Lindau syndrome 2010-07-01 no assertion criteria provided literature only

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