ClinVar Miner

Submissions for variant NM_198156.3(VHL):c.341-3237del (rs1553619952)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000528640 SCV000626874 pathogenic Von Hippel-Lindau syndrome 2017-07-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the VHL gene (p.Asp126Valfs*33). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acids of the VHL protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with VHL-related disease. This truncation disrupts a significant portion of the VHL elongin C binding domain (PMID: 14987375), which is required for protein stability and tumor suppressive activity (PMID: 10900011). Different truncations downstream of this variant (p.Asn141Lysfs*3, p.161Arg*, deletion of exon 3) have been determined to be pathogenic (PMID: 19270817, 10567493, 7987306, 12114495, 25867206, 15300849, 9829911, 9829912, 9452032, 8956040, 21362373, 18446368, 24301059, Invitae). This suggests that deletion of this region of the VHL protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001384431 SCV001583927 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2017-06-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the VHL gene (p.Asp126Valfs*33). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acids of the VHL protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with VHL-related disease. This truncation disrupts a significant portion of the VHL elongin C binding domain (PMID: 14987375), which is required for protein stability and tumor suppressive activity (PMID: 10900011). Different truncations downstream of this variant (p.Asn141Lysfs*3, p.161Arg*, deletion of exon 3) have been determined to be pathogenic (PMID: 19270817, 10567493, 7987306, 12114495, 25867206, 15300849, 9829911, 9829912, 9452032, 8956040, 21362373, 18446368, 24301059, Invitae). This suggests that deletion of this region of the VHL protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. 3

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