Submissions for variant NM_000551.4(VHL):c.320G>A (p.Arg107His)

dbSNP: rs193922609

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492448	SCV000580972	pathogenic	Hereditary cancer-predisposing syndrome	2015-08-13	criteria provided, single submitter	clinical testing	The p.R107H pathogenic mutation (also known as c.320G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 320. The arginine at codon 107 is replaced by histidine, an amino acid with highly similar properties.This alteration has been reported in a woman meeting clinical diagnostic criteria for VHL and segregated with disease in her family (BoedekerCC et al. JClinEndocrinolMetab. 2009 Jun;94(6):1938-44). In addition, three other alterations at the same codon (p.R107C, p.R107P and p.R107G) have been associated with VHL and pheochromocytoma(DandanellM et al.BMC Med. Genet. 2012 ; 13():54;Siu WK et al.Chin. Med. J. 2011 Jan; 124(2):237-41;StolleC et al.Hum.Mutat. 1998;12(6):417-23). Based on the available evidence to date, p.R107H is classified as a pathogenic mutation.<br />
Invitae	RCV001379601	SCV001577428	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-08-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg107 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12000816, 12624160, 21362373, 22799452; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 223184). This missense change has been observed in individuals with VHL-related conditions (PMID: 12202531, 19336503; external communication). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 107 of the VHL protein (p.Arg107His).
PreventionGenetics, part of Exact Sciences	RCV003897458	SCV004709396	pathogenic	VHL-related disorder	2023-12-02	criteria provided, single submitter	clinical testing	The VHL c.320G>A variant is predicted to result in the amino acid substitution p.Arg107His. This variant was reported in an individual with Von Hippel-Lindau syndrome (Dollfus et al 2002. PubMed ID: 12202531). Other missense changes at the same amino acid position, p.Arg107Pro, p.Arg107His, and p.Arg107Gly have all been reported in patients with Von Hippel-Lindau syndrome (Rocha JC et al 2003. PubMed ID: 12624160; Boedeker CC et al 2009. PubMed ID: 19336503; Stolle C et al 1998. PubMed ID: 9829911; Neumann HP et al 2002. PubMed ID: 12000816). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208864	SCV000264706	likely pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing