Submissions for variant NM_000551.4(VHL):c.278G>A (p.Gly93Asp)

dbSNP: rs1553619440

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586256	SCV000697495	pathogenic	Von Hippel-Lindau syndrome	2016-02-04	criteria provided, single submitter	clinical testing	Variant summary: c.278G>A affects a conserved nucleotide, resulting in amino acid change from Gly to Asp. 4/4 in-silico tools predict this variant to be damaging. This variant was not found in 101892 control chromosomes. This variant has been reported in multiple VHL pts and classified as pathgenic by literatures. Variants G93R, G93C, and G93S are all listed as disease mutation in HGMD and have been reported in multiple literatures, suggesting the codon 93 is a hypermutable amino acid and a hotspot for mutations. Taken together, this variant was classified as a Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000586256	SCV000897795	pathogenic	Von Hippel-Lindau syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV001853983	SCV002161398	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-04-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly93 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 12000816; Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 14556007, 14973063). 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: 496054). This variant is also known as c.491G>A (p.Gly164Asp). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 16314641; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 93 of the VHL protein (p.Gly93Asp).