Submissions for variant NM_000551.4(VHL):c.347T>G (p.Leu116Arg)

dbSNP: rs879254230

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236337	SCV000293915	uncertain significance	not provided	2016-02-05	criteria provided, single submitter	clinical testing	This variant is denoted VHL c.347T>G at the cDNA level, p.Leu116Arg (L116R) at the protein level, and results in the change of a Leucine to an Arginine (CTT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. VHL Leu116Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Leu116Arg occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located in the beta-domain and is involved in binding to CCT complex (Yuen 2009, UniProt). While computational modeling has predicted VHL Leu116Arg to be functionally significant (Rajasekaran 2008), in-house in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether VHL Leu116Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818505	SCV000959123	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 116 of the VHL protein (p.Leu116Arg). 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: 246383). 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%. 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	RCV002450737	SCV002617595	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-11	criteria provided, single submitter	clinical testing	The p.L116R variant (also known as c.347T>G), located in coding exon 2 of the VHL gene, results from a T to G substitution at nucleotide position 347. The leucine at codon 116 is replaced by arginine, an amino acid with dissimilar properties. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Gadd MS et al. Nat Chem Biol, 2017 05;13:514-521). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.