Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

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
More

Likely Benign

Met criteria codes 2
BS1 BS2_Supporting
Not Met criteria codes 1
PS4

Evidence Links 0

Expert Panel

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).
Met criteria codes
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).
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.
Not Met criteria codes
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.
Curation History
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