Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000551.4(VHL):c.422dup (p.Asn141fs)

CA16611276

411979 (ClinVar)

Gene: VHL

Condition: von Hippel-Lindau disease

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3edb89db-b42c-4081-a05d-026362ccc657

Approved on: 2024-06-25

Published on: 2024-06-25

HGVS expressions

NM_000551.4:c.422dup

NM_000551.4(VHL):c.422dup (p.Asn141fs)

NC_000003.12:g.10146595dup

CM000665.2:g.10146595dup

NC_000003.11:g.10188279dup

CM000665.1:g.10188279dup

NC_000003.10:g.10163279dup

NG_008212.3:g.9961dup

ENST00000696142.1:c.*99dup

ENST00000696143.1:c.600-3192dup

ENST00000696153.1:c.422dup

ENST00000256474.3:c.422dup

ENST00000256474.2:c.422dup

ENST00000345392.2:c.341-3192dup

ENST00000477538.1:n.558dup

NM_000551.3:c.422dup

NM_198156.2:c.341-3192dup

NM_001354723.1:c.*18-3192dup

NM_001354723.2:c.*18-3192dup

NM_198156.3:c.341-3192dup

Pathogenic

PS4_Supporting PVS1 PM2_Supporting

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

VHL VCEP

The NM_000551.4(VHL):c.422dup (p.Asn141fs) is a frameshift variant affecting position 141. This variant is not expected to undergo nonsense mediated decay, but is in a functional domain critical to the protein function (nuclear export domain) (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Two commercial laboratories report cases. Case 1 (0.5 points): displayed bilateral renal masses and likely pheochromocytoma, with a small Paraganglioma panel run. Case 2 (0.5): Multiple renal tumors in 40s, no other family history known, and a 13-gene panel was run for renal cancers (PS4_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) 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).

PS4_Supporting

Two commercial laboratories report cases. Case 1 (0.5 points): displayed bilateral renal masses and likely pheochromocytoma, with a small Paraganglioma panel run. Case 2 (0.5 points): Multiple renal tumors in 40s, no other family history known. Subject had a 13-gene panel for renal cancers.

PVS1

This variant is not expected to undergo nonsense mediated decay, but is in a functional domain critical to the protein function (nuclear export domain) (PVS1).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

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