Submissions for variant NM_000551.4(VHL):c.430G>T (p.Gly144Ter)

dbSNP: rs869025650

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692586	SCV000820416	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2020-01-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Arg161*) that lies downstream of this variant has been determined to be pathogenic (PMID: 19602254, 18446368, 24301059, 14722919, 24206762). Additionally, this truncation disrupts a significant portion of the VHL elongin binding domain (PMID: 14987375), which is required for protein stability and tumor suppressive activity (PMID: 10900011). Experimental studies have shown that missense substitutions in this domain (p.Arg161Gln, p.Cys162Trp, p.Arg167Gly, p.Arg167Trp, p.Arg167Gln) impair protein function in vitro (PMID: 25371412, 21715564, 17350623, 19602254, 15574766, 19030229, 19252526, 14973063), indicating that the amino acid residues disrupted by this truncating variant are important for protein function. This variant has been reported in a family affected with pheochromocytoma (PMID: 9829911). This variant is also known as 643G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 223208). 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.Gly144*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 70 amino acids of the VHL protein.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208850	SCV000264734	likely pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing