Submissions for variant NM_000551.4(VHL):c.540_543del (p.Val181fs)

dbSNP: rs869025664

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000805034	SCV000944976	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2018-11-05	criteria provided, single submitter	clinical testing	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.Val181Glyfs*20). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acids of the VHL protein. This variant has been observed in the literature in a family affected with von Hippel-Lindau syndrome (PMID: 9829911). This variant is also known as 753_756delCGTC in the literature. ClinVar contains an entry for this variant (Variation ID: 223230). 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, 8707293). This suggests that variants that disrupt this region of the protein are likely to be causative of disease.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208795	SCV000264767	uncertain significance	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing