Variant: NM_000551.4(VHL):c.586A>T (p.Lys196Ter)

CA020507

196284 (ClinVar)

Gene: VHL

Condition: von Hippel-Lindau disease

Inheritance Mode: Autosomal dominant inheritance

UUID: 0b8bd98c-075b-42a9-9ea0-c44456d12a52

Approved on: 2024-06-25

Published on: 2024-06-25

HGVS expressions

NM_000551.4:c.586A>T
NM_000551.4(VHL):c.586A>T (p.Lys196Ter)
NC_000003.12:g.10149909A>T
CM000665.2:g.10149909A>T
NC_000003.11:g.10191593A>T
CM000665.1:g.10191593A>T
NC_000003.10:g.10166593A>T
NG_008212.3:g.13275A>T
ENST00000696142.1:c.*263A>T
ENST00000696143.1:c.722A>T
ENST00000696153.1:c.697A>T
ENST00000256474.3:c.586A>T
ENST00000256474.2:c.586A>T
ENST00000345392.2:c.463A>T
ENST00000477538.1:n.722A>T
NM_000551.3:c.586A>T
NM_198156.2:c.463A>T
NM_001354723.1:c.*140A>T
NM_001354723.2:c.*140A>T
NM_198156.3:c.463A>T

Pathogenic

• Met criteria codes: PVS1 PS4_Supporting PM2_Supporting

Expert Panel

VHL VCEP

Criteria Specification Information

Criteria Specification: ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.0.0

Evidence submitted by expert panel

VHL VCEP

The NM_000551.3(VHL):c.586A>T (p.Lys196Ter) variant in VHL is a truncating mutation that terminates the VHL protein at position 196, which resides in the second Beta domain (PVS1). One proband has been identified with this variant, and has a family history of VHL and clinical features of VHL (CNS hemangioblastoma, renal cell carcinoma in a female of reported age 17 (Hwang et al (PMID:25078357)). One case meeting Danish VHL criteria equates to supporting evidence (PS4_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024).

Met criteria codes

• PVS1: This variant in VHL is a nonsense variant predicted to cause a premature stop codon in a biologically-relevant exon. It is not predicted to cause nonsense mediated decay but it is in a critical domain (second beta domain) of the protein. (PVS1).
• PS4_Supporting: Hwang et al (PMID:25078357) updated clinical details of a subject published by Cho et al (PMID:19270817). The subject is a 17yo female with family history of VHL disease, a CNS hemangioblastoma and renal cell carcinoma as well as other related but not described manifestations. This subject meets the Danish VHL criteria. One subject meeting Danish VHL criteria is supporting evidence per the ClinGen VHL VCEP (PS4_Supporting).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).