Submissions for variant NM_000551.4(VHL):c.629G>A (p.Arg210Gln)

gnomAD frequency: 0.00013  dbSNP: rs138780791

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115743	SCV000149652	likely benign	not provided	2019-02-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26580448)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627744	SCV000153873	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 210 of the VHL protein (p.Arg210Gln). This variant is present in population databases (rs138780791, gnomAD 0.01%). This missense change has been observed in individual(s) with a glioma (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 127828). 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.
Counsyl	RCV000119153	SCV000488335	uncertain significance	Von Hippel-Lindau syndrome	2016-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000492305	SCV000580977	likely benign	Hereditary cancer-predisposing syndrome	2019-02-28	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	RCV000119153	SCV001306569	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000119153	SCV002526037	uncertain significance	Von Hippel-Lindau syndrome	2022-04-20	criteria provided, single submitter	clinical testing	The VHL c.629G>A (p.Arg210Gln) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in an individual with pediatric glioma (PMID: 26580448). To our knowledge, this variant has not been reported in individuals with Von Hippel-Lindau disease. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: no criteria applied.
Sema4, Sema4	RCV000492305	SCV002534198	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-05	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267856	SCV002552409	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000119153	SCV004841677	uncertain significance	Von Hippel-Lindau syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 210 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 been reported in an individual affected with glioma (PMID: 26580448). This variant has been identified in 17/282174 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.
PreventionGenetics, part of Exact Sciences	RCV003935103	SCV004749582	uncertain significance	VHL-related disorder	2024-02-21	no assertion criteria provided	clinical testing	The VHL c.629G>A variant is predicted to result in the amino acid substitution p.Arg210Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD. In ClinVar this variant has conflicting interpretations of pathogenicity including uncertain significance and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/127828). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.