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.89G>A (p.Gly30Glu)

CA16617781

418538 (ClinVar)

Gene: VHL

Condition: von Hippel-Lindau disease

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 95e42e40-98b1-4795-857e-f2677975ddd4

Approved on: 2024-06-25

Published on: 2024-06-25

HGVS expressions

NM_000551.4:c.89G>A

NM_000551.4(VHL):c.89G>A (p.Gly30Glu)

NC_000003.12:g.10141936G>A

CM000665.2:g.10141936G>A

NC_000003.11:g.10183620G>A

CM000665.1:g.10183620G>A

NC_000003.10:g.10158620G>A

NG_008212.3:g.5302G>A

ENST00000696142.1:c.89G>A

ENST00000696143.1:c.89G>A

ENST00000696153.1:c.89G>A

ENST00000256474.3:c.89G>A

ENST00000256474.2:c.89G>A

ENST00000345392.2:c.89G>A

NM_000551.3:c.89G>A

NM_198156.2:c.89G>A

NM_001354723.1:c.89G>A

NM_001354723.2:c.89G>A

NM_198156.3:c.89G>A

Likely Benign

BS2_Supporting BS1

PS4

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 variant NM_000551.4(VHL):c.89G>A (p.Gly30Glu) is a missense variant predicted to cause substitution of Glycine by Glutamic Acid at position 30. This is prior to the second start site at codon 54. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0001073 (10/50204 from Admixed American Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1). In addition, one commercial laboratory reports at least 3 cases over 60+ with no VHL spectrum tumors, and another commercial laboratory reports too many cases over 65+ without VHL spectrum tumors to review (of 35 cases with no VHL spectrum tumors). The VHL VCEP has determined this meets (BS2_Supporting) due to the number of cases, ages and lack of information on full VHL screening/phenotyping. In summary, this variant meets the criteria to be classified as Likely Benign 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).

BS2_Supporting

The variant NM_000551.4(VHL):c.89G>A (p.Gly30Glu) is a missense variant predicted to cause substitution of Glycine by Glutamic Acid at position 30. This is prior to the second start site at codon 54. In gnomAD (non-cancer) v2.1.1, the total frequency is 0.00004052, and the highest subpopulation frequency is 0.0002025 in Latino/Admixed American. This is higher than the >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In addition, one commercial laboratory reports at least 3 cases over 60+ with no VHL spectrum tumors, and another commercial laboratory reports too many cases over 65+ without VHL spectrum tumors to review (of 35 cases with no VHL spectrum tumors). The VHL VCEP has determined this meets (BS2_Supporting) due to the number of cases, ages and lack of information on full VHL screening/phenotyping.

BS1

The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0001073 (10/50204 from Admixed American Population). This is higher than the ClinGen VHL VCEP threshold of >=0.0000156 (0.00156%) threshold expected for VHL disease (BS1).

PS4

Across three commercial laboratories, there are a total of 66 cases with only 1 case harboring VHL spectrum tumors. In addition, there are at least 3 cases over 60 years+ that are do not harbor VHL spectrum tumors from one reporting laboratory, and another had too many cases over 65+ to review. PS4_NotMet.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.