Submissions for variant NM_000551.4(VHL):c.475A>T (p.Lys159Ter)

dbSNP: rs1575932011

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002007406	SCV002235347	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2021-09-26	criteria provided, single submitter	clinical testing	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.Glu189Lysfs*13) have been determined to be pathogenic (PMID: 9452032, 24132471; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This premature translational stop signal has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys159*) in the VHL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the VHL protein.
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV003329425	SCV004036037	pathogenic	Von Hippel-Lindau syndrome	2023-09-25	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP4;PM2;PVS1
PreventionGenetics, part of Exact Sciences	RCV004728985	SCV005337593	pathogenic	VHL-related disorder	2024-06-11	no assertion criteria provided	clinical testing	The VHL c.475A>T variant is predicted to result in premature protein termination (p.Lys159*). To our knowledge, this variant has not been reported in the literature. This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1451803/). Nonsense variants in VHL are expected to be pathogenic. This variant is interpreted as pathogenic.