Submissions for variant NM_000551.4(VHL):c.89G>A (p.Gly30Glu)

gnomAD frequency: 0.00006  dbSNP: rs1064793290

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001712442	SCV000565654	likely benign	not provided	2021-01-10	criteria provided, single submitter	clinical testing
Invitae	RCV000696976	SCV000825562	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 30 of the VHL protein (p.Gly30Glu). 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: 418538). 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	RCV001018619	SCV001179876	likely benign	Hereditary cancer-predisposing syndrome	2021-08-13	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.
Baylor Genetics	RCV001294070	SCV001482870	uncertain significance	Von Hippel-Lindau syndrome	2019-02-21	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001712442	SCV002774877	uncertain significance	not provided	2021-07-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001712442	SCV004146914	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing	VHL: PM2:Supporting, BP4
PreventionGenetics, part of Exact Sciences	RCV003900013	SCV004717003	uncertain significance	VHL-related disorder	2024-01-16	criteria provided, single submitter	clinical testing	The VHL c.89G>A variant is predicted to result in the amino acid substitution p.Gly30Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/). 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	RCV001294070	SCV004827698	uncertain significance	Von Hippel-Lindau syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 30 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 been identified in 7/176170 chromosomes 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.