Submissions for variant NM_000551.4(VHL):c.277G>A (p.Gly93Ser)

dbSNP: rs5030808

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698471	SCV000827137	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-12-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 2237). This variant is also known as c.490G>A. This missense change has been observed in individual(s) with von Hippel-Lindau (VHL) syndrome (PMID: 8707293, 9329368, 12000816, 17661816, 17922902). In at least one individual the variant was observed to be de novo. 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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 93 of the VHL protein (p.Gly93Ser).
Ambry Genetics	RCV002433441	SCV002751677	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-05	criteria provided, single submitter	clinical testing	The p.G93S pathogenic mutation (also known as c.277G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 277. The glycine at codon 93 is replaced by serine, an amino acid with similar properties. This alteration has been reported in families with Von Hippel-Lindau (VHL) with pheochromocytomas as well as in individuals with isolated pheochromocytomas (Zbar B et al. Hum Mutat. 1996;8(4):348-57; Neumann HP et al. N Engl J Med. 2002 May 9;346(19):1459-66). Of note, this alteration is also known as c.490G>A in published 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.
Baylor Genetics	RCV003460405	SCV004208794	pathogenic	Chuvash polycythemia	2021-11-30	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV004998072	SCV005622336	pathogenic	not provided	2024-08-05	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with VHLS and/or pheochromocytoma and has been reported to occur de novo in multiple individuals. This variant is also referred to as c.490G>A in published literature. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein.
OMIM	RCV000002325	SCV000022483	pathogenic	Pheochromocytoma	2002-05-09	no assertion criteria provided	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208813	SCV000264693	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing
Clinical Genomics Labs, University Health Network	RCV000208813	SCV002601727	pathogenic	Von Hippel-Lindau syndrome	2021-12-15	no assertion criteria provided	clinical testing