Submissions for variant NM_000551.4(VHL):c.541G>A (p.Val181Ile)

dbSNP: rs878854127

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229544	SCV000285502	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 181 of the VHL protein (p.Val181Ile). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 238111). 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 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	RCV000662874	SCV000785768	uncertain significance	Von Hippel-Lindau syndrome	2017-11-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257540	SCV002534184	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-27	criteria provided, single submitter	curation
Ambry Genetics	RCV002257540	SCV002649351	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-07	criteria provided, single submitter	clinical testing	The p.V181I variant (also known as c.541G>A), located in coding exon 3 of the VHL gene, results from a G to A substitution at nucleotide position 541. The valine at codon 181 is replaced by isoleucine, 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. Based on the available evidence, the clinical significance of this variant remains unclear.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465580	SCV002760272	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
GeneDx	RCV003153527	SCV003842933	uncertain significance	not provided	2023-03-16	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28893800, 30981987, 18195360)
All of Us Research Program, National Institutes of Health	RCV000662874	SCV004841657	uncertain significance	Von Hippel-Lindau syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 181 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 hereditary cancer in the literature. This variant has been identified in 1/251418 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.