Variant: NM_000551.4(VHL):c.583C>T (p.Gln195Ter)

CA70052558

428794 (ClinVar)

Gene: VHL

Condition: von Hippel-Lindau disease

Inheritance Mode: Autosomal dominant inheritance

UUID: 506678db-35be-41e0-9c07-5feac64181ec

Approved on: 2024-06-25

Published on: 2024-06-25

HGVS expressions

NM_000551.4:c.583C>T
NM_000551.4(VHL):c.583C>T (p.Gln195Ter)
NC_000003.12:g.10149906C>T
CM000665.2:g.10149906C>T
NC_000003.11:g.10191590C>T
CM000665.1:g.10191590C>T
NC_000003.10:g.10166590C>T
NG_008212.3:g.13272C>T
ENST00000696142.1:c.*260C>T
ENST00000696143.1:c.719C>T
ENST00000696153.1:c.694C>T
ENST00000256474.3:c.583C>T
ENST00000256474.2:c.583C>T
ENST00000345392.2:c.460C>T
ENST00000477538.1:n.719C>T
NM_000551.3:c.583C>T
NM_198156.2:c.460C>T
NM_001354723.1:c.*137C>T
NM_001354723.2:c.*137C>T
NM_198156.3:c.460C>T

Pathogenic

• Met criteria codes: PS4_Moderate PM2_Supporting PVS1

• Not Met criteria codes: BA1 BS1

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.583C>T (p.Gln195Ter) variant in VHL is a truncating mutation that terminates the VHL protein at position 195, which resides in the second Beta domain (PVS1). A total of 13 probands or families have been identified with this variant, and they have clinical features of VHL (some Type 1, some Type 2A). 11 probands or families were identified in the following PMIDs: 20660572, 8707293, 23298237, 21463266, 9408111, 17661816, 25867206, 17024664. CIViC EIDs (https://civicdb.org) are: 5472, 5360, 5691, 8693, 9255, 5097, 6623, 5134. Two additional affected cases were contributed by a commercial laboratory, with VHL phenotypes and one case has segregation data. The case total of 13 equates to moderate evidence (PS4_Moderate). 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

• PS4_Moderate: A total of 13 probands or families have been identified with this variant, and they have clinical features of VHL (some Type 1, some Type 2A). 11 probands or families were identified in the following PMIDs: 20660572, 8707293, 23298237, 21463266, 9408111, 17661816, 25867206, 17024664. CIViC EIDs (https://civicdb.org) are: 5472, 5360, 5691, 8693, 9255, 5097, 6623, 5134. 2 additional affected cases were contributed by a commercial laboratory. The case total of 13 equates to moderate evidence (PS4_Moderate).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• PVS1: This variant terminates the VHL protein at position 195, which resides in the second Beta domain.

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline