What evidence supports HNF1B p.Arg177Ter—and what is still missing?
Build an ACMG/AMP research worksheet from an exact allele, a PVS1 suggestion and an unsuccessful population-frequency lookup.
Ask your AI client
Use GeneFoundry to build an ACMG/AMP evidence worksheet for HNF1B NM_000458.4:c.529C>T (p.Arg177Ter), ClinVar VCV000012635, in autosomal dominant renal cysts and diabetes syndrome. Resolve the GRCh38 allele, retrieve its ClinVar record and gnomAD frequency, inspect AutoPVS1 and VEP, and confirm ClinGen validity and dosage context. Separate source classifications from candidate criteria, identify missing evidence and avoid double counting. Do not produce an autonomous final classification.
The result
ClinVar reports Pathogenic with two review stars for the resolved GRCh38 allele. AutoPVS1 suggests VeryStrong loss-of-function evidence, but this remains a candidate for expert review. The gnomAD lookup returned not_found, so no population-frequency criterion is assigned.
| Source / observation | Captured result |
|---|---|
| ClinVar identity | VCV000012635 · NM_000458.4:c.529C>T · p.Arg177Ter |
| ClinVar aggregate classification | Pathogenic · 2/4 stars · criteria provided, multiple submitters, no conflicts · 7 submitters |
| ClinVar dates | Last evaluated 7 March 2025; weekly release 31 August 2026 |
| ClinGen gene-disease context | HNF1B–renal cysts and diabetes syndrome (MONDO:0007669) · autosomal dominant · Definitive |
| ClinGen mechanism context | Haploinsufficiency score 3: sufficient evidence for dosage pathogenicity |
| AutoPVS1 | NM_000458.4 · exon 2/9 · predicted NMD · NF1 path · VeryStrong (source: inferred) |
| VEP | stop_gained; ENST00000617811.5:c.529C>T / ENSP00000480291.1:p.Arg177Ter among returned transcripts |
| gnomAD 4.1.1 / r4 | Resolver: zero matches. Frequency call: not_found. No AF, AC, AN or coverage returned. |
| Criterion / evidence | Status in this worksheet | What still needs review |
|---|---|---|
| PVS1 | Candidate; AutoPVS1 suggests VeryStrong, not independently assigned | Confirm relevant transcript/exon expression, predicted NMD and HNF1B loss-of-function mechanism for this disease. Apply current SVI and any applicable gene-specific specification. |
| PM2 | Unassigned | No frequency or callable allele number was returned. Verify site coverage and ancestry-relevant rarity against an appropriate disease threshold; general SVI guidance reduces PM2 to Supporting. |
| PP3 / PM4 | Not added for the same predicted truncation | VEP stop_gained, CADD and the NMD prediction do not supply independent support to stack on PVS1 for the same effect. |
| PP5 / source assertion | Not used | ClinVar’s aggregate classification is reported separately. Inspect the underlying evidence; a reputable-source label is not an independent pathogenic criterion. |
| PS2 / PM6 / PP1 / PP4 | Unassigned | No parental testing, confirmed de novo event, segregation or sufficiently specific patient phenotype was provided. |
| PS3 / PS4 | Unassigned | No validated functional assay or independently reviewed case-enrichment evidence was retrieved. |
| Overall classification | Not assigned | Complete and critically review the missing evidence before applying an ACMG/AMP combination framework. |
This is an actual execution with a documented failed lookup, not a successful frequency measurement. VEP also returned an empty frequencies array; that does not repair the missing gnomAD denominator.
The worksheet focuses on renal cysts and diabetes syndrome. ClinVar also returned a composite condition label; its aggregate must not be silently generalized to every listed condition.
The separate ClinGen validity and dosage records provide disease and mechanism context. They do not prove the variant’s effect independently of AutoPVS1.
AutoPVS1 is an automated, HTML-derived assessment and its final strength was marked inferred. Predicted NMD is not an experimentally demonstrated RNA result.
How GeneFoundry got this
Resolve the exact ClinVar allele
Read VCV000012635 and preserve its transcript, GRCh38 allele, submitted classification and condition context.
clinvar_get_variant{ "identifier": "VCV000012635", "id_type": "vcv", "response_mode": "full" }Confirm the disease relationship
Check HNF1B specifically for autosomal dominant renal cysts and diabetes syndrome.
clingen_get_gene_validity{ "gene_symbol": "HNF1B", "response_mode": "standard" }Check the assembly-matched population identifier
Search the ClinVar-resolved GRCh38 allele in gnomAD r4.
gnomad_resolve_variant_id{ "query": "17-37739455-G-A", "dataset": "gnomad_r4", "enrich": true, "limit": 5 }Record the unavailable frequency
Request frequency for that exact allele and retain the not_found response.
gnomad_get_variant_frequencies{ "variant_id": "17-37739455-G-A", "dataset": "gnomad_r4", "response_mode": "compact" }Inspect the automated loss-of-function suggestion
Run AutoPVS1 for the same hg38 allele and inspect its transcript-specific decision path.
autopvs1_get_variant_pvs1_data{ "variant_id": "17-37739455-G-A", "genome_build": "hg38", "response_mode": "standard", "meta_mode": "compact" }Cross-check consequence without counting it twice
Annotate the same GRCh38 allele with VEP and preserve versioned transcript consequences.
vep_annotate_variant{ "variant": "17-37739455-G-A", "assembly": "GRCh38", "response_mode": "standard", "transcripts": "auto" }Review the loss-of-function mechanism
Read ClinGen dosage sensitivity before interpreting the PVS1 suggestion.
clingen_get_gene_dosage{ "gene_symbol": "HNF1B", "response_mode": "full" }
This educational worksheet is not a complete ACMG/AMP assessment, clinical classification or patient report. No genotype, phenotype, segregation, de novo or case-level evidence was supplied.
The exact gnomAD lookup failed with not_found. No allele frequency, coverage or allele number was returned; absence and PM2 cannot be inferred from that failure.
The automated PVS1 strength is a source suggestion marked inferred. Assignment requires review of gene-disease mechanism, biologically relevant transcript and nonsense-mediated decay.