Submissions for variant NM_000551.4(VHL):c.34G>C (p.Glu12Gln)

gnomAD frequency: 0.00001  dbSNP: rs1064794788

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485486	SCV000569940	uncertain significance	not provided	2016-04-08	criteria provided, single submitter	clinical testing	This variant is denoted VHL c.34G>C at the cDNA level, p.Glu12Gln (E12Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. VHL Glu12Gln was not observed in approximately 5,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. VHL Glu12Gln occurs at a position that is not conserved and is located within a region involved in the binding of the ODD region of HIF-alpha subunits (Yuen 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether VHL Glu12Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000808373	SCV000948481	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 12 of the VHL protein (p.Glu12Gln). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 420914). 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. 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.
Ambry Genetics	RCV001020464	SCV001181949	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-31	criteria provided, single submitter	clinical testing	The p.E12Q variant (also known as c.34G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 34. The glutamic acid at codon 12 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is 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.
Baylor Genetics	RCV003464013	SCV004208771	uncertain significance	Chuvash polycythemia	2023-06-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003340	SCV004832048	uncertain significance	Von Hippel-Lindau syndrome	2023-07-22	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 12 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 1/141144 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.