Variant classification summary

NM_000551.3:c.-77C>T

VHL · NP_000542.1:p.? · NM_000551.3

GRCh37: chr3:10183455 C>T · GRCh38: chr3:10141771 C>T

Gene: VHL Transcript: NM_000551.3

Final call

Benign

BA1 stand-alone benign BS1 strong

Variant details

Gene

VHL

Transcript

NM_000551.3

Protein

NP_000542.1:p.?

gnomAD AF

0.004923082712627982 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

ClinVar classifies this variant as Benign (Variation ID 256649; 2 clinical laboratories) and Likely benign (1 clinical laboratory).

5

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.

6

Under VHL VCEP v1.1.0 combination rules (Rule 17), BA1 alone is sufficient for a Benign classification. Overall classification: Benign.

Final determination: Rule17 in the ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.1.0 v1.1.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_000551.3:c.-77C>T is a substitution 77 nucleotides upstream of the initiation codon in the 5'UTR. PVS1 is reserved for null variants (nonsense, frameshift, canonical splice). This variant does not alter protein sequence and does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations and VHL VCEP guidance.	pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 requires a different nucleotide change at the same amino acid position that has been classified as pathogenic. This is a 5'UTR variant with no protein consequence; there is no amino acid change to compare. No VCEP-classified pathogenic variant exists at this non-coding position.	cspec
PS2	Not assessed	No de novo observations have been reported for NM_000551.3:c.-77C>T. PS2/PM6 requires confirmed or assumed de novo occurrence with a VHL-spectrum phenotype.
PS3	Not assessed	No functional studies have been performed on NM_000551.3:c.-77C>T. The VHL VCEP functional assay documentation spreadsheet (HIF degradation, VBC complex stability, fibronectin binding/deposition assays) does not contain an entry for this variant. PS3 cannot be assigned without experimental evidence.	vcep_vhl_functional_assay_svi_documentation
PS4	Not assessed	No proband data with VHL-spectrum phenotype has been identified for NM_000551.3:c.-77C>T. The ClinVar submissions cite general guideline references rather than variant-specific case reports. PS4 requires proband counting with VCEP phenotype scoring, and no qualifying probands are available.	clinvar
PS5	Not met	ClinVar classifies NM_000551.3:c.-77C>T as Benign (2 clinical laboratories) and Likely benign (1 clinical laboratory). PS5 requires a reputable source to report the variant as pathogenic, which is not the case.	clinvar
PM1	N/A	VHL VCEP PM1 rule applies to putative missense variants in known germline hotspots, key functional domains, or somatic hotspots with cancerhotspots.org evidence. NM_000551.3:c.-77C>T is a 5'UTR substitution; it is not a missense variant and does not fall within a coding region or functional domain.	cspec
PM2	Not met	NM_000551.3:c.-77C>T is common in population databases. In gnomAD v4.1, the GroupMax Filtering Allele Frequency is 0.08882 (8.88%), far exceeding the VCEP PM2_Supporting threshold of ≤0.000156% (≤1.56×10⁻⁶). The variant is observed in 7,326 alleles including 332 homozygotes.	gnomad_v4
PM5	N/A	PM5 requires a novel missense change at an amino acid residue where a different pathogenic missense has been established. NM_000551.3:c.-77C>T is a 5'UTR substitution with no protein consequence. There is no amino acid residue to compare. pm5_candidates confirms variant is not eligible for classic PM5.	pm5_candidates cspec
PM6	Not assessed	No assumed or confirmed de novo observations have been reported for NM_000551.3:c.-77C>T. PM6 requires de novo occurrence (without confirmation of parentage) with a VHL-spectrum phenotype per VCEP scoring.
PP1	Not assessed	No segregation data are available for NM_000551.3:c.-77C>T. PP1 requires co-segregation in affected family members with VHL-spectrum disease across meioses.
PP2	N/A	VHL VCEP specifies PP2 is not applicable for this gene. gnomAD shows VHL is not intolerant to missense variation (Z score = -0.39), and benign/common missense variants exist. Additionally, this is a 5'UTR substitution, not a missense variant.	cspec
PP3	Not met	VHL VCEP PP3 requires REVEL ≥0.664 for missense variants or SpliceAI >0.5 + VarSeak class 4/5 for splice variants. NM_000551.3:c.-77C>T is a 5'UTR variant; REVEL is not applicable (no missense change). SpliceAI returned null scores (no splice prediction generated for this variant). No computational evidence supports a damaging effect.	spliceai cspec
PP4	N/A	VHL VCEP specifies PP4 is not applicable. The VCEP instructs combining phenotype assessment with PS4 to avoid double counting probands.	cspec
PP5	N/A	VHL VCEP specifies PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Met	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_v2 gnomad_v4 cspec
BS1	Met	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 cspec
BS2	Not assessed	VHL VCEP BS2 requires at least 3 individuals aged ≥65 years, unaffected, with full phenotyping and screening for absence of VHL-related cancers. While gnomAD v4.1 shows 332 homozygotes for this variant, suggesting tolerance of homozygous state, individual-level clinical phenotype data meeting VCEP BS2 criteria are not available from population databases.	gnomad_v4
BS3	Not assessed	No functional studies demonstrating a benign effect have been reported for NM_000551.3:c.-77C>T. The VHL VCEP functional assay documentation spreadsheet does not list this variant in any approved assay (VBC complex stability, HIF degradation, fibronectin binding/deposition). BS3 requires well-established functional studies showing no damaging effect.	vcep_vhl_functional_assay_svi_documentation
BS4	Not assessed	No segregation data are available for NM_000551.3:c.-77C>T. BS4 requires lack of segregation in affected members of families per VHL VCEP specifications. The high population frequency itself suggests lack of segregation with disease, but formal family-based segregation data are not available.
BP1	N/A	VHL VCEP specifies BP1 is not applicable for this gene. Truncating variants account for only a portion of disease-causing variants in VHL.	cspec
BP2	Not assessed	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. gnomAD v4.1 shows 332 homozygotes for c.-77C>T, strongly suggesting homozygosity is tolerated, but individual clinical data confirming absence of VHL disease or congenital polycythemia are not available.	gnomad_v4
BP3	N/A	NM_000551.3:c.-77C>T is a single-nucleotide substitution in the 5'UTR, not an in-frame deletion/insertion in a repetitive region. BP3 applies only to the 8x GXEEX repeat motif in VHL p30 (AA14-AA48), which is within the coding sequence. This variant lies 77 nucleotides upstream of the start codon.
BP4	Not met	VHL VCEP BP4 requires concordance of SpliceAI ≤0.1 and VarSeak Class 1/2 to assess lack of splicing impact. SpliceAI returned null scores for NM_000551.3:c.-77C>T, indicating no splice prediction could be generated for this 5'UTR variant. Without a SpliceAI score ≤0.1, BP4 cannot be applied per VCEP specifications.	spliceai cspec
BP5	Not assessed	No co-occurrence data with pathogenic variants in other genes are available for NM_000551.3:c.-77C>T. VHL VCEP BP5 requires two or more co-occurrences with pathogenic variants in a different gene that fully explain the patient's phenotype, with specific phenotype criteria.
BP6	N/A	VHL VCEP specifies BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	Not met	VHL VCEP BP7 requires that BP4 be met first (lack of splicing impact) and that the PhyloP score be ≤0.2. BP4 was not met because SpliceAI returned null scores for this variant. Therefore BP7 cannot be applied. Additionally, PhyloP conservation data for this position have not been evaluated.	cspec spliceai

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