ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.435_436del (p.Gln145fs) (rs869025652)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000208807 SCV000264736 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
Invitae RCV000706591 SCV000835650 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-01-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the VHL gene (p.Gln145Hisfs*28). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 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 von Hippel-Lindau syndrome (PMID: 7977367). This variant is also known as c.648_649delGC in the literature. ClinVar contains an entry for this variant (Variation ID: 223210). 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.

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