Submissions for variant NM_000551.4(VHL):c.28G>A (p.Glu10Lys)

gnomAD frequency: 0.00006  dbSNP: rs1057519261

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000476548	SCV000553396	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-09	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 10 of the VHL protein (p.Glu10Lys). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 374982). 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	RCV001016912	SCV001177918	likely benign	Hereditary cancer-predisposing syndrome	2021-09-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001584111	SCV001810951	uncertain significance	not provided	2023-06-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with neuroblastoma (Zhang et al., 2015); This variant is associated with the following publications: (PMID: 26580448)
Sema4, Sema4	RCV001016912	SCV002534156	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-02	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002488864	SCV002781531	uncertain significance	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2021-09-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463824	SCV004208748	uncertain significance	Chuvash polycythemia	2023-09-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001584111	SCV004221482	uncertain significance	not provided	2023-02-02	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00018 (3/16348 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in an individual with medulloblastoma (PMID: 26580448 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415643	SCV000493823	uncertain significance	Von Hippel-Lindau syndrome	2015-12-04	no assertion criteria provided	clinical testing