Submissions for variant NM_000551.4(VHL):c.486C>A (p.Cys162Ter)

dbSNP: rs5030622

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001061348	SCV001226086	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2019-11-25	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 28388566). ClinVar contains an entry for this variant (Variation ID: 223226). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the VHL gene (p.Cys162*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acids of the VHL protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the VHL protein. Other variant(s) that disrupt this region (p.Ser183*) have been determined to be pathogenic (PMID: 8707293, 10567493, 11309459). This suggests that variants that disrupt this region of the protein are likely to be causative of disease.
Ambry Genetics	RCV003165513	SCV003888333	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-03	criteria provided, single submitter	clinical testing	The p.C162* pathogenic mutation (also known as c.486C>A), located in coding exon 3 of the VHL gene, results from a C to A substitution at nucleotide position 486. This changes the amino acid from a cysteine to a stop codon within coding exon 3. This alteration occurs at the 3' terminus of theVHL gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 23.9% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with VHL-related disease (Fagundes GFC et al. J Endocr Soc, 2019 Sep;3:1682-1692; Peng S et al. Oncotarget, 2017 Jun;8:38456-38465). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208851	SCV000264760	likely pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing