Submissions for variant NM_000551.4(VHL):c.95A>G (p.Glu32Gly)

gnomAD frequency: 0.00001  dbSNP: rs786203104

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166262	SCV000217042	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	The p.E32G variant (also known as c.95A>G), located in coding exon 1 of the VHL gene, results from an A to G substitution at nucleotide position 95. The glutamic acid at codon 32 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000230870	SCV000285506	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 32 of the VHL protein (p.Glu32Gly). This variant is present in population databases (rs786203104, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 186635). 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 not expected to disrupt VHL protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001558212	SCV001780112	uncertain significance	not provided	2022-06-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV000166262	SCV002534203	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-01	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002485030	SCV002776436	uncertain significance	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2021-11-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995493	SCV004825445	uncertain significance	Von Hippel-Lindau syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 32 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with VHL-related disorders in the literature. This variant has been identified in 4/145516 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.