Submissions for variant NM_000551.4(VHL):c.572A>C (p.His191Pro)

dbSNP: rs370050374

Total submissions: 4

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200136	SCV000254654	likely pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 191 of the VHL protein (p.His191Pro). This variant is present in population databases (rs370050374, gnomAD 0.0009%). 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: 182984). 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%. This variant disrupts the p.His191 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12844285, 23403324). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics	RCV002345555	SCV002650208	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-13	criteria provided, single submitter	clinical testing	The p.H191P variant (also known as c.572A>C), located in coding exon 3 of the VHL gene, results from an A to C substitution at nucleotide position 572. The histidine at codon 191 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003462112	SCV004206475	uncertain significance	Chuvash polycythemia	2023-10-05	criteria provided, single submitter	clinical testing