ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.430G>T (p.Gly144Ter) (rs869025650)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000692586 SCV000820416 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-03-13 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). 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). 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. For these reasons, this variant has been classified as Pathogenic.
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

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