Submissions for variant NM_000551.4(VHL):c.614G>T (p.Arg205Leu)

dbSNP: rs777130107

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526063	SCV000626913	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-08-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 205 of the VHL protein (p.Arg205Leu). This variant is not present in population databases (gnomAD no frequency). 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: 456592). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on VHL 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.
Ambry Genetics	RCV002358439	SCV002654930	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-02	criteria provided, single submitter	clinical testing	The p.R205L variant (also known as c.614G>T), located in coding exon 3 of the VHL gene, results from a G to T substitution at nucleotide position 614. The arginine at codon 205 is replaced by leucine, an amino acid with dissimilar properties. In an algorithmic assessment of missense alteration severity in the VHL protein, incorporating aggregation propensity, protein-protein interactions, secondary structure, conformational flexibility, solvent accessibility, protein stability, post-translational modification and translational rate, the p.R205L alteration was considered to be low risk (Fields FR et al. PLoS One, 2020 Nov;15:e0234100). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004003778	SCV004841676	uncertain significance	Von Hippel-Lindau syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 205 of the VHL protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.