Variant: NM_000551.4(VHL):c.634G>T (p.Gly212Ter)

CA351756706

440404 (ClinVar)

Gene: VHL

Condition: von Hippel-Lindau disease

Inheritance Mode: Autosomal dominant inheritance

UUID: 1e6ad747-83ac-4daf-a155-7d6a7eae39ef

Approved on: 2024-06-25

Published on: 2024-06-25

HGVS expressions

NM_000551.4:c.634G>T
NM_000551.4(VHL):c.634G>T (p.Gly212Ter)
NC_000003.12:g.10149957G>T
CM000665.2:g.10149957G>T
NC_000003.11:g.10191641G>T
CM000665.1:g.10191641G>T
NC_000003.10:g.10166641G>T
NG_008212.3:g.13323G>T
ENST00000696142.1:c.*311G>T
ENST00000696143.1:c.770G>T
ENST00000696153.1:c.745G>T
ENST00000256474.3:c.634G>T
ENST00000256474.2:c.634G>T
ENST00000345392.2:c.511G>T
ENST00000477538.1:n.770G>T
NM_000551.3:c.634G>T
NM_198156.2:c.511G>T
NM_001354723.1:c.*188G>T
NM_001354723.2:c.*188G>T
NM_198156.3:c.511G>T

Uncertain Significance

• Met criteria codes: PVS1_Moderate

• Not Met criteria codes: BS1 PS4

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 variant NM_000551.4(VHL):c.634G>T (p.Gly212Ter) is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove <10% of the protein. It is within 2 amino acids from the last in VHL, and AA 205-213 have unknown or uncertain function in the protein (PVS1_Moderate). The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00001063 (3/74922 from African/African American Population). This is lower than the ClinGen VHL VCEP threshold expected for VHL disease, of >=0.0000156 (0.00156%) for BS1, and therefore does not meet any criterion (BS1, BA1, PM2_Supporting are not met). A total of 12 cases are reported from 3 commercial laboratories, and none of the cases harbor VHL spectrum tumors (PS4_NotMet). There are no additional cases reported in published literature. In summary, this variant meets the criteria to be classified as Uncertain 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).

Met criteria codes

• PVS1_Moderate: This variant is a nonsense variant that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay and remove <10% of the protein. It is within 2 amino acids from the last in VHL, and AA 205-213 have unknown or uncertain function in the protein (PVS1_Moderate).

Not Met criteria codes

• BS1: The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.00001063 (3/74922 from African/African American Population). This is lower than the ClinGen VHL VCEP threshold expected for VHL disease, of >=0.0000156 (0.00156%) for BS1, and therefore does not meet any criterion (BS1, BA1, PM2_Supporting are not met).
• PS4: Three commercial laboratories report 12 cases total with none harboring VHL spectrum tumors.