NM_000551.3:c.-77C>T meets BA1 (Stand-Alone) under VHL VCEP v1.1.0: GroupMax Filtering Allele Frequency of 8.88% in gnomAD v4.1 far exceeds the BA1 threshold of 0.0156%, establishing this variant as benign.1 NM_000551.3:c.-77C>T also meets BS1 (Strong): GroupMax Filtering Allele Frequency of 8.88% far exceeds the BS1 threshold of 0.00156%, further supporting a benign classification.2 NM_000551.3:c.-77C>T is observed in 332 homozygotes in gnomAD v4.1 and 36 homozygotes in gnomAD v2.1, incompatible with autosomal dominant von Hippel-Lindau disease with high penetrance.3 ClinVar classifies this variant as Benign (Variation ID 256649; 2 clinical laboratories) and Likely benign (1 clinical laboratory).4 No pathogenic or likely pathogenic criteria were met. PM2 was not met (frequency far exceeds PM2_Supporting threshold). PP3 was not met (no computational evidence of deleterious effect). PVS1, PS1, PM1, and PM5 are not applicable to this 5'UTR variant.5 Under VHL VCEP v1.1.0 combination rules (Rule 17), BA1 alone is sufficient for a Benign classification. Overall classification: Benign.6
VHL
Final classification
Benign
VHL c.-77C>T · p.?
VHL
NM_000551.3:c.-77C>T meets BA1 (Stand-Alone) under VHL VCEP v1.1.0: GroupMax Filtering Allele Frequency of 8.88% in gnomAD v4.1 far exceeds the BA1 threshold of 0.0156%, establishing this variant as benign.
ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.1.0 v1.1.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BS1 strong; maps to Benign.
Classification rationale
BA1BS1
Benign
VHL c.-77C>T
BA1 + BS1
→
Benign
Gene diagram
· NM_000551.3 · variants mapped to exon structure
VHL
NM_000551.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
NM_000551.3:c.-77C>T has a GroupMax Filtering Allele Frequency of 0.0888 (8.88%) in gnomAD v4.1 and 0.0856 (8.56%) in gnomAD v2.1, far exceeding the VHL VCEP BA1 threshold of ≥0.0156% (≥1.56×10⁻⁴). This allele frequency is incompatible with a highly penetrant autosomal dominant disorder such as von Hippel-Lindau disease. The variant is also observed in 332 homozygotes in gnomAD v4.1.
gnomAD v4.1: grpmax FAF=0.08882 (8.88%)7326 alleles332 homozygotes
✓
BS1
strong
Benign
NM_000551.3:c.-77C>T has a GroupMax Filtering Allele Frequency of 0.0888 (8.88%) in gnomAD v4.1, far exceeding the VHL VCEP BS1 threshold of ≥0.00156% (≥1.56×10⁻⁵). The allele frequency is too high for a rare disease like von Hippel-Lindau syndrome.
gnomAD v4.1: grpmax FAF=0.08882 (8.88%)7326/1488092 allelesVCEP BS1 threshold: ≥0.0000156 (0.00156%) GroupMax FAF
Assessed · not applied
Pathogenic
PS2
No de novo observations have been reported for NM_000551.3:c.-77C>T.
PS3
No functional studies have been performed on NM_000551.3:c.-77C>T.
PS4
No proband data with VHL-spectrum phenotype has been identified for NM_000551.3:c.-77C>T.
PM2
NM_000551.3:c.-77C>T is common in population databases.
PM6
No assumed or confirmed de novo observations have been reported for NM_000551.3:c.-77C>T.
PP1
No segregation data are available for NM_000551.3:c.-77C>T.
PP3
VHL VCEP PP3 requires REVEL ≥0.664 for missense variants or SpliceAI >0.5 + VarSeak class 4/5 for splice variants.
Benign
BS2
VHL VCEP BS2 requires at least 3 individuals aged ≥65 years, unaffected, with full phenotyping and screening for absence of VHL-related cancers.
BS3
No functional studies demonstrating a benign effect have been reported for NM_000551.3:c.-77C>T.
BS4
No segregation data are available for NM_000551.3:c.-77C>T.
BP2
VHL VCEP BP2 can be applied when a variant is observed in trans with a known pathogenic variant, in the homozygous state without VHL disease, or in cis/unknown phase with multiple pathogenic VHL variants.
BP4
VHL VCEP BP4 requires concordance of SpliceAI ≤0.1 and VarSeak Class 1/2 to assess lack of splicing impact.
BP5
No co-occurrence data with pathogenic variants in other genes are available for NM_000551.3:c.-77C>T.
BP7
VHL VCEP BP7 requires that BP4 be met first (lack of splicing impact) and that the PhyloP score be ≤0.2.
N/A · 10
PVS1 · PS1 · PM1 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00492308; MAF= 0.49231%, 7326/1488092 alleles, homozygotes = 332) and has highest observed frequency in the African/African American population (AF= 0.0906683; MAF= 9.06683%, 6471/71370 alleles, homozygotes = 325); grpmax FAF= 0.0888216.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.0257254; MAF= 2.57254%, 805/31292 alleles, homozygotes = 36) and has highest observed frequency in the African/African American population (AF= 0.0908356; MAF= 9.08356%, 787/8664 alleles, homozygotes = 36); grpmax FAF= 0.0855752.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.49%
· 7326 / 1,488,092
332 hom · FAF 8.9%
332 hom · FAF 8.9%
African/African American 6471 / 71,370 |
9.1% 325 hom |
Admixed American 320 / 49,082 |
0.65% 4 hom |
Remaining individuals 367 / 57,666 |
0.64% 3 hom |
Middle Eastern 9 / 4,228 |
0.21% |
European (non-Finnish) 153 / 1,098,908 |
0.014% |
South Asian 5 / 82,202 |
0.0061% |
Ashkenazi Jewish 1 / 27,836 |
0.0036% |
+ 3 not observed (European (Finnish), Amish, East Asian)
gnomAD v2.1
2.6%
· 805 / 31,292
36 hom · FAF 8.6%
36 hom · FAF 8.6%
African/African American 787 / 8,664 |
9.1% 36 hom |
Admixed American 8 / 848 |
0.94% |
Remaining individuals 7 / 1,086 |
0.64% |
European (non-Finnish) 3 / 15,376 |
0.02% |
+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 256649)
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV104558409, n = 2 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
20664475 ↗
The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer.
CLINVAR
23788249 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
CLINVAR
25356965 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
24893135 ↗
Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
CLINVAR