Submissions for variant NM_000551.4(VHL):c.151G>A (p.Glu51Lys)

dbSNP: rs1480825246

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000818739	SCV000959369	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 51 of the VHL protein (p.Glu51Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 661344). 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 not expected to disrupt VHL protein function with a negative 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	RCV002390679	SCV002708616	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	The p.E51K variant (also known as c.151G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 151. The glutamic acid at codon 51 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003413650	SCV004112892	uncertain significance	VHL-related disorder	2024-02-02	criteria provided, single submitter	clinical testing	The VHL c.151G>A variant is predicted to result in the amino acid substitution p.Glu51Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0013% of alleles in individuals of European (non-Finnish) descent in gnomAD and it has been classified as uncertain by other institutions in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/661344/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004001814	SCV004838454	uncertain significance	Von Hippel-Lindau syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 51 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with VHL-related disorders 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.