Submissions for variant NM_000551.4(VHL):c.277G>C (p.Gly93Arg)

dbSNP: rs5030808

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035237	SCV001198557	likely pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-03-11	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly93 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8707293, 9329368, 12000816, 17661816, 17922902). 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: 223174). This variant is also known as 490G>C (p.Gly93Arg). This missense change has been observed in individual(s) with VHL-related conditions (PMID: 20660572, 23660872; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 93 of the VHL protein (p.Gly93Arg).
Ambry Genetics	RCV002433917	SCV002751678	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-02-19	criteria provided, single submitter	clinical testing	The p.G93R variant (also known as c.277G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 277. The glycine at codon 93 is replaced by arginine, an amino acid with dissimilar properties. This alteration, also designated as 490G>C in the literature, has been reported in multiple individuals having or suspected of having a diagnosis of VHL (Klein B et al. Hum. Genet. 2001 May;108:376-84; de Cubas AA et al. Endocr. Relat. Cancer. 2013 Aug;20:477-93; Bausch B et al. J Transl Med Epidemiol. 2014 2(1):1019.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 majority of available evidence to date, this variant is likely to be pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208861	SCV000264692	likely pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing