Submissions for variant NM_000551.4(VHL):c.218A>G (p.Gln73Arg)

dbSNP: rs1295818809

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneKor MSA	RCV000708763	SCV000822210	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000708763	SCV001175445	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-05	criteria provided, single submitter	clinical testing	The p.Q73R variant (also known as c.218A>G), located in coding exon 1 of the VHL gene, results from an A to G substitution at nucleotide position 218. The glutamine at codon 73 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059124	SCV001223733	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-07-26	criteria provided, single submitter	clinical testing	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. 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: 584568). This missense change has been observed in individual(s) with clinical features of VHL-related conditions (PMID: 31159747). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 73 of the VHL protein (p.Gln73Arg).
GeneDx	RCV002469274	SCV002765300	uncertain significance	not provided	2022-06-16	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; Observed in an individual undergoing multi-gene hereditary cancer genetic testing (Tsaousis 2019); This variant is associated with the following publications: (PMID: 31159747)
PreventionGenetics, part of Exact Sciences	RCV003403638	SCV004103602	uncertain significance	VHL-related disorder	2023-09-18	criteria provided, single submitter	clinical testing	The VHL c.218A>G variant is predicted to result in the amino acid substitution p.Gln73Arg. This variant has been reported with uncertain significance in a large study of individuals with personal or family history of breast and/or ovarian cancer (Table S5 in Tsaousis et al. 2019. PubMed ID: 31159747). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been classified as uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/584568/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003460991	SCV004206465	uncertain significance	Chuvash polycythemia	2023-10-16	criteria provided, single submitter	clinical testing