Submissions for variant NM_000551.4(VHL):c.544A>G (p.Arg182Gly)

gnomAD frequency: 0.00001  dbSNP: rs778205243

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204757	SCV000261369	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 182 of the VHL protein (p.Arg182Gly). This variant is present in population databases (rs778205243, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of hereditary erythrocytosis (PMID: 29790589). ClinVar contains an entry for this variant (Variation ID: 220655). 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.
GeneDx	RCV000235376	SCV000293307	uncertain significance	not provided	2018-04-13	criteria provided, single submitter	clinical testing	This variant is denoted VHL c.544A>G at the cDNA level, p.Arg182Gly (R182G) at the protein level, and results in the change of an Arginine to a Glycine (AGG>GGG). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. VHL Arg182Gly was observed at an allele frequency of 0.01% (5/34418) in individuals of Latino ancestry in large population cohorts (Lek 2016). Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. VHL Arg182Gly is located in the alpha domain (Yuen 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether VHL Arg182Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000663322	SCV000786593	uncertain significance	Von Hippel-Lindau syndrome	2018-06-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000235376	SCV000805356	uncertain significance	not provided	2018-03-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001024120	SCV001186082	likely benign	Hereditary cancer-predisposing syndrome	2023-06-08	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.
Illumina Laboratory Services, Illumina	RCV000663322	SCV001304547	likely benign	Von Hippel-Lindau syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
All of Us Research Program, National Institutes of Health	RCV000663322	SCV004841658	uncertain significance	Von Hippel-Lindau syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 182 of the VHL protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in heterozygous state in an individual affected with suspected hereditary erythrocytosis (PMID: 29790589). This variant has been identified in 6/282832 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.
Baylor Genetics	RCV004567477	SCV005055804	uncertain significance	Chuvash polycythemia	2023-12-22	criteria provided, single submitter	clinical testing