Submissions for variant NM_000551.4(VHL):c.275A>T (p.Asp92Val)

gnomAD frequency: 0.00001  dbSNP: rs749091984

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163954	SCV000214551	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-20	criteria provided, single submitter	clinical testing	The p.D92V variant (also known as c.275A>T), located in coding exon 1 of the VHL gene, results from an A to T substitution at nucleotide position 275. The aspartic acid at codon 92 is replaced by valine, an amino acid with highly dissimilar properties. While this variant has not been reported in the literature to date, a different alteration at the same codon, p.D92G, was observed in an individual with an endolymphatic sac tumor, cerebellar hemangioblastoma, and renal and pancreatic cysts (Codreanu CM et al. Otol Neurotol. 2010 Jun;31:660-4). This amino acid position is not 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.
Counsyl	RCV000412307	SCV000488452	uncertain significance	Von Hippel-Lindau syndrome	2016-03-31	criteria provided, single submitter	clinical testing
Invitae	RCV000525495	SCV000626892	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 92 of the VHL protein (p.Asp92Val). This variant is present in population databases (rs749091984, gnomAD 0.001%). This missense change has been observed in individual(s) with clinical features of von Hippel-Lindau (VHL) syndrome (PMID: 31368132). ClinVar contains an entry for this variant (Variation ID: 184664). 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 with a positive predictive value of 80%. 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.
PreventionGenetics, part of Exact Sciences	RCV003389706	SCV000805335	uncertain significance	VHL-related disorder	2023-07-18	criteria provided, single submitter	clinical testing	The VHL c.275A>T variant is predicted to result in the amino acid substitution p.Asp92Val. This variant was reported in two individuals with Von Hippel-Lindau syndrome (Table S1, Salama et al. 2019. PubMed ID: 31368132). This variant is reported in 1 of ~223,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/3-10183806-A-T). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/184664/). An alternate nucleotide affecting the same amino acid (p.Asp92Gly) has been reported in an individual with Von Hippel-Lindau syndrome (Codreanu et al. 2010. PubMed ID: 20351605). At this time, the clinical significance of the c.275A>T (p.Asp92Val) variant is uncertain due to the absence of conclusive functional and genetic evidence.
Fulgent Genetics, Fulgent Genetics	RCV002485013	SCV002790591	uncertain significance	Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma	2022-01-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000679028	SCV003924646	uncertain significance	not provided	2023-05-11	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as c.488A>T; p.(D163V) or p.(D133V); Observed in individuals with pheochromocytoma/paraganglioma and unspecified central nervous system tumor (Salama et al., 2019); This variant is associated with the following publications: (PMID: 20351605, 31368132)
Baylor Genetics	RCV003462123	SCV004208754	uncertain significance	Chuvash polycythemia	2023-08-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000412307	SCV004822935	uncertain significance	Von Hippel-Lindau syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 92 of the VHL protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with VHL-associated cancer or who have a VHL diagnosis (PMID: 31368132). This variant has been identified in 1/223138 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.