Submissions for variant NM_000551.4(VHL):c.235C>T (p.Arg79Cys)

gnomAD frequency: 0.00001  dbSNP: rs200885420

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000231302	SCV000285492	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the VHL protein (p.Arg79Cys). This variant is present in population databases (rs200885420, gnomAD 0.04%). This missense change has been observed in individual(s) with congenital polycythemia (PMID: 15642680). ClinVar contains an entry for this variant (Variation ID: 161400). 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 expected to disrupt VHL protein function with a positive 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.
GeneDx	RCV000235492	SCV000293496	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Identified in the compound heterozygous state in an individual with congenital polycythemia (Bento et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.448C>T; p.R150C. p.R120C; This variant is associated with the following publications: (PMID: 16210343, 25637381, 18538455, 17454194, 27651169, 23178531, 19295544, 20151405, 24729484, 23538339, 15642680)
Counsyl	RCV000412420	SCV000488813	uncertain significance	Von Hippel-Lindau syndrome	2016-06-24	criteria provided, single submitter	clinical testing
Mendelics	RCV000412420	SCV001136310	uncertain significance	Von Hippel-Lindau syndrome	2023-04-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444611	SCV002734507	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	The p.R79C variant (also known as c.235C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 235. The arginine at codon 79 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the compound heterozygous state with another alteration in VHL in a patient with congenital polycythemia (Bento MC et al. Haematologica, 2005 Jan;90:128-9). This alteration has also been reported as a likely benign variant in an exome cohort, but clinical history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003407569	SCV004109237	uncertain significance	VHL-related disorder	2022-12-14	criteria provided, single submitter	clinical testing	The VHL c.235C>T variant is predicted to result in the amino acid substitution p.Arg79Cys. This variant has been reported in the compound heterozygous state in an individual with congenital polycythemia (Bento et al. 2005. PubMed ID: 15642680). This variant is reported in 0.052% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-10183766-C-T). In ClinVar, this variant has conflicting interpretations of benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/161400/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003467206	SCV004206469	uncertain significance	Chuvash polycythemia	2023-10-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000412420	SCV004828208	uncertain significance	Von Hippel-Lindau syndrome	2023-11-30	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148920	SCV000190676	likely benign	Polycythemia	2014-06-01	no assertion criteria provided	research