Submissions for variant NM_000551.4(VHL):c.628C>T (p.Arg210Trp)

gnomAD frequency: 0.00003  dbSNP: rs774380450

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204248	SCV000261324	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 210 of the VHL protein (p.Arg210Trp). This variant is present in population databases (rs774380450, 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: 220627). 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	RCV000568942	SCV000675808	likely benign	Hereditary cancer-predisposing syndrome	2023-01-05	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.
Counsyl	RCV000662950	SCV000785911	uncertain significance	Von Hippel-Lindau syndrome	2018-01-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001582712	SCV001812859	uncertain significance	not provided	2021-01-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 9067265, 22549840, 20151405)
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV002467673	SCV002764245	likely pathogenic	Maffucci syndrome		criteria provided, single submitter	research
Baylor Genetics	RCV003468958	SCV004208757	uncertain significance	Chuvash polycythemia	2023-08-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001582712	SCV004221486	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported as a germline variant in the published literature. The frequency of this variant in the general population, 0.00016 (3/18374 chromosomes in East Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. 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.