Submissions for variant NM_000551.4(VHL):c.641G>T (p.Ter214Leu)

dbSNP: rs869025668

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765350	SCV004569526	likely pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This sequence change disrupts the translational stop signal of the VHL mRNA. It is expected to extend the length of the VHL protein by 14 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 20560986). This variant is also known as p.*214Leuext*15. ClinVar contains an entry for this variant (Variation ID: 223236). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this protein extension affects VHL function (PMID: 20560986). This variant results in an extension of the VHL protein. Other variant(s) that result in a similarly extended protein product (p.*214Cysext*14) have been observed in individuals with VHL-related disease (PMID: 20560986). This suggests that these extensions may be clinically significant. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208844	SCV000264777	likely pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing