Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000466046 | SCV000553389 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2022-06-26 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg167 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7987306, 9829912, 21463266, 25563310). 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: 2219). This variant is also known as 712C>G, p.Arg238Gly. This missense change has been observed in individual(s) with von Hippel–Lindau disease (VHL) or clinical features of VHL (PMID: 7987306, 19574279; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 167 of the VHL protein (p.Arg167Gly). |
| Genomic Diagnostic Laboratory, |
RCV000002304 | SCV000897839 | pathogenic | Von Hippel-Lindau syndrome | 2018-08-01 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002336073 | SCV002640461 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-10-26 | criteria provided, single submitter | clinical testing | The p.R167G pathogenic mutation (also known as c.499C>G), located in coding exon 3 of the VHL gene, results from a C to G substitution at nucleotide position 499. The arginine at codon 167 is replaced by glycine, an amino acid with dissimilar properties. This pathogenic mutation has been reported in multiple individual's with clinical features of VHL (Crossey PA et al. Hum Mol Genet. 1994 Aug;3:1303-8; Gergics P et al. Eur J Endocrinol. 2009 Sep;161:495-502; Krauss T et al. Endocr Relat Cancer. 2018 09;25:783-793). Two other alterations at the same codon, p.R167W (c.499C>T) and p.R167Q (c.500G>A), have been described in numerous VHL families (Babinska A et al. Neuro Endocrinol. Lett. 2015 Dec;36:517-20; Lee JS et al. BMC Med. Genet. 2016 Jul;17:48; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175(4):311-23; Chew WHW et al. Mol Genet Genomic Med. 2017 Sep;5(5):602-607; Zbar B et al. Hum. Mutat. 1996;8:348-57; Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67:758-62; Zhou J et al. Pathol. Int. 2010 Jun;60:452-8; Wang X et al. Urology. 2014 Mar;83:675.e1-5; Wong M et al. Chin J Cancer. 2016 Aug;35:79). Available evidence suggests that germline mutations at codon 167 convey an increased risk for developing pheochromocytoma (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3:1303-8; Chen F et al. Hum. Mut. 1995;5:66-75; Zbar B et al. Hum. Mutat. 1996;8:348-57; Olschwang S et al. Hum. Mut. 1998;12:424-30; Fishbein L et al. Ann. Surg. Oncol. 2013 May;20:1444-50). Of note, this variant may be referred to as c.712C>G (p.R238G) in some older literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| OMIM | RCV000002304 | SCV000022462 | pathogenic | Von Hippel-Lindau syndrome | 1995-06-01 | no assertion criteria provided | literature only |