Submissions for variant NM_000551.4(VHL):c.71G>A (p.Gly24Asp)

gnomAD frequency: 0.00001  dbSNP: rs878854129

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231328	SCV000285504	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 24 of the VHL protein (p.Gly24Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 238113). 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.
Counsyl	RCV000412262	SCV000488910	uncertain significance	Von Hippel-Lindau syndrome	2016-07-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001026150	SCV001188473	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-27	criteria provided, single submitter	clinical testing	The p.G24D variant (also known as c.71G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 71. The glycine at codon 24 is replaced by aspartic acid, an amino acid with 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.
Baylor Genetics	RCV003463663	SCV004208764	uncertain significance	Chuvash polycythemia	2023-07-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000412262	SCV004830547	uncertain significance	Von Hippel-Lindau syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 24 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 1/144544 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.