ClinVar Genomic variation as it relates to human health

Variant summary: VHL c.154G>T (p.Glu52X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Glu55fsX12, p.Gly57fsX75, p.Val62fsX5). The variant allele was found at a frequency of 4.1e-05 in 24438 control chromosomes. c.154G>T has been reported in the literature in an individual with haemangioblastoma of the central nervous system (Leonardi_2011) as well as other cancer phenotypes (Susswein_2015, Mandelker_2017). These data do not allow any conclusion about variant significance. A functional study showed the variant to undergoing proteasome-dependent degradation (Schoenfeld_2000). However, there is some evidence that a second transcript, in which the variant occurs upstream of the start codon, provides sufficient VHL protein-protein interactions and tumor suppressor activity (Iliopoulos_1998, Schoenfeld_1998). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS - possibly pathogenic.

Nonsense variant in a gene for which a downstream in-frame ATG produces an alternate clinically-relevant isoform, pVHL19, that may result in a functional protein (Iliopoulos 1998, Schoenfeld 1998, Blankenship 1999); Observed in individuals with hemangioblastoma, renal cancer, or pancreatic cancer in published literature, but also in several individuals without personal history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx (Leonardi 2011, Johns 2017, Carlo 2018, Sculco 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21463266, 27651169, 26681312, 28526081, 28454591, 28539463, 28873162, 29790589, 28492532, 29978187, 32994724, 10900011, 34566400, 35032816, 9751722, 9671762, 10102622)

This sequence change creates a premature translational stop signal (p.Glu52*) in the VHL gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 54 has the potential to rescue this variant. 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 premature translational stop signal has been observed in individual(s) with VHL-related conditions (PMID: 26681312, 27651169, 28454591). ClinVar contains an entry for this variant (Variation ID: 182982). Several studies have shown that the VHL protein created from a downstream methionine located at codon 54 is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722). 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.

This variant changes 1 nucleotide in exon 1 of the VHL gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. However, there is a naturally occurring VHL protein isoform that has start of translation at methionine 54 and appears to retain tumor suppressor activity (PMID: 9671762, 9751722, 10102622), which may ameliorate the deleterious effects of this N-terminal frameshift. To our knowledge, functional studies have not been reported for this variant. This variant has been reported three individuals affected with VHL-associated clinical features including one individual affected with central nervous system hemangioblastoma and pancreatic cyst (PMID: 21463266), an individual affected with multiple retinal and cerebellar hemangioblastoma (PMID: 34566400), and an individual affected with renal cell carcinoma (PMID: 28873162). This variant also has been reported in one individual each affected with pancreatic and breast cancer (PMID: 26681312, 28454591), two individuals affected with erythrocytosis (PMID: 27651169, 29790589) and an individual affected with malignant pleural mesothelioma (PMID: 35032816). This variant has been identified in 4/222880 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of VHL function is a known mechanism of disease (clinicalgenome.org). 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.

The p.Glu52X variant in VHL has been reported in at least 1 sporadic case with VHL-associated tumors (Leonardi 2011). It has also been identified in 3/94886 European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs373068386). This nonsense variant leads to a premature termination codon at position 52, which is predicted to lead to a truncated or absent protein. However, two isoforms of the VHL protein are expressed in humans: the full length protein (pVHL30) and a shorter isoform (pVHL19), which is translated from the methionine residue at position 54 of pVHL30 (Robinson 2014). Both isoforms are reported to have tumor suppressor abilities (Blankenship 1999). The p.Glu52X variant would only be expected to impact the pVHL30 isoform, meaning that a functional VHL tumor suppressor (pVHL19) may still be produced. A mouse model lacking the long isoform of VHL did not have overt phenotypes, supporting that loss of pVHL30 may not be sufficient to cause von Hippel-Lindau (VHL) syndrome (Frew 2013). Nevertheless, several studies suggest that the pVHL19 and pVHL30 have unique cellular functions (Frew 2013, Minervini 2015), and loss of the pVHL30 isoform may lead to clinical manifestations. Only two other studies have reported loss of funtion (LoF) variants that impact only the pVHL30 isoform (Olschwang 1998, Fu 2015), and additional data would provide evidence to support the association of "pVHL30 only" LoF variants to VHL syndrome. In summary, while there is some suspicion for a pathogenic role due to its predicted impact, the clinical significance of the p.Glu52X variant is uncertain.

The p.E52* variant (also known as c.154G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 154. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This alteration was reported in a patient diagnosed with Von Hippel-Lindau syndrome (VHLS) and developed a retinal capillary hemangioblastoma and in an individual with a hemangioblastoma of the central nervous system and a pancreatic cyst/ tumor (Murro V et al. Mol Vis. 2021 Sep;27:542-554; Leonardi E et al. Ann. Hum. Genet. 2011 Jul; 75(4):483-96). It has also been observed in an individual with advanced renal cell carcinoma (Carlo MI et al. JAMA Oncol. 2018 09;4:1228-1235). This alteration has additionally been identified in a cohort of erythrocytosis patients (Camps C et al. Haematologica. 2016 Nov;101:1306-1318). Premature stop codons are typically deleterious in nature; however, an alternate initiation codon exists two residues downstream of this alteration, and is reported to result in a biologically active isoform, known as VHL19 (Iliopoulos O et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Sep; 95(20):11661-6. Schoenfeld A et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Jul; 95(15):8817-22). In addition, this alteration has been seen internally in multiple individuals without classic clinical features of VHLS (Ambry internal data). Since supporting evidence for this variant is conflicting at this time, the clinical significance of this variant remains unclear.