ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.572A>C (p.His191Pro) (rs370050374)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161093 SCV000211828 uncertain significance not provided 2014-07-30 criteria provided, single submitter clinical testing This variant is denoted VHL c.572A>C at the cDNA level, p.His191Pro (H191P) at the protein level, and results in the change of a Histidine to a Proline (CAC>CCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. VHL His191Pro was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Histidine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL His191Pro occurs at a position that is well conserved in mammals and is located in the alpha domain (Yuen 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether VHL His191Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000200136 SCV000254654 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 191 of the VHL protein (p.His191Pro). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and proline. This variant is present in population databases (rs370050374, ExAC 0.002%). This variant has not been reported in the literature in individuals with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 182984). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense variant involving the same codon (p.His191Asp) has been reported as homozygous in individuals affected with polycythemia (PMID: 12844285, 23403324) and has been shown to affect VHL protein function (PMID: 21685897, 23403324, 27651169), which suggests that the His191 residue may play an important role in protein function. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.