Submissions for variant NM_000551.4(VHL):c.463G>A (p.Val155Met)

dbSNP: rs869025659

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515564	SCV003525019	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-03-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 155 of the VHL protein (p.Val155Met). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 8634692, 20233476). This variant is also known as c.676G>A. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the VHL protein in which other variant(s) (p.Arg161Gln) have been determined to be pathogenic (PMID: 7728151, 9829911, 12000816, 14767570, 15300849, 20120764, 21362373, 23842656, 24707167). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in activation of a cryptic splice site and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 223219).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596112	SCV005090551	likely pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208799	SCV000264747	uncertain significance	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing