LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-29
Case ID: NM_000492.4_c.1652G_A_20261029_121522
Framework: ACMG/AMP 2015
Variant classification summary

NM_000492.4:c.1652G>A

CFTR  · NP_000483.3:p.(Gly551Asp)  · NM_000492.4
GRCh37: chr7:117227860 G>A  ·  GRCh38: chr7:117587806 G>A
Gene: CFTR Transcript: NM_000492.4
Final call
Pathogenic
PS3 strong PM1 moderate PM3 supporting PP3 strong PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
CFTR
Transcript
NM_000492.4
Protein
NP_000483.3:p.(Gly551Asp)
gnomAD AF
0.00039202627259431926 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS3 strong—independent cellular assays demonstrate severe G551D CFTR gating and chloride-transport defects.
2
Pathogenic: PM1 moderate—G551D lies in CFTR's conserved first nucleotide-binding fold, a critical functional domain.
3
Pathogenic: PM3 supporting—affected individuals were G551D/F508del compound heterozygotes, establishing the variants in trans.
4
Pathogenic: PP3 strong—REVEL 0.99 exceeds the generic strong threshold of 0.932 for missense variants.
5
Pathogenic: PP5 supporting—the exact variant has a Pathogenic CFTR2 expert-panel classification in ClinVar.
Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS3 and PP3) satisfy the Pathogenic combination rule; PM1, PM3, and PP5 provide additional support.
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 Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not assessed Not assessed: p.Gly551Asp is established as disease-associated, but no independent alternate nucleotide change producing Gly551Asp is documented.
PMID:2236053 PMID:1379413 clinvar
PS2 Not assessed Not assessed: no proband-specific parental testing documents confirmed maternity and paternity, a de novo variant, and no family history.
PS3 Met Met at strong strength: G551D showed approximately 120-fold lower channel open probability than wild type and concordant chloride-transport defects across independent cellular assays.
PMID:17353351 PMID:19846789 PMID:22293084 PMID:21083385
PS4 Not assessed Not assessed: 3/40 versus gnomAD NFE gives exploratory OR 158.87 (95% CI 48.85–516.67), but ancestry-matched case-control evidence is unavailable.
PMID:2236053 PMID:1379413 gnomad_v4
PM1 Met Met: residue 551 lies in CFTR's first nucleotide-binding fold, a conserved functional domain, while gnomAD v4.1 frequency is 0.000392 with no homozygotes.
PMID:2236053 PMID:1379413 gnomad_v4
PM2 Not met Not met: gnomAD v4.1 overall AF 0.000392026 exceeds the <=0.0001 PM2 supporting threshold.
gnomad_v2 gnomad_v4
PM3 Met Met at supporting strength: 79 affected individuals were G551D/delta F508 compound heterozygotes, establishing G551D in trans with pathogenic F508del.
PMID:1379413
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no different pathogenic missense substitution at CFTR residue 551 is documented in the available evidence.
pm5_candidates PMID:2236053 PMID:1379413
PM6 Not assessed Not assessed: no proband-specific observation supports an assumed de novo variant with parental maternity or paternity unconfirmed.
PP1 Not assessed Not assessed: no pedigree or individual-level results show this variant co-segregating with disease in multiple affected family members.
PP2 Not assessed Not assessed: CFTR missense disease is documented, but the required low benign-missense rate and gene-level mechanism evidence are not established.
PMID:2236053 PMID:1379413 gnomad_v4
PP3 Met Met, strong: missense REVEL score 0.99 exceeds the generic PP3 strong threshold of 0.932.
revel
PP4 Not assessed Not assessed: the individual patient's phenotype and family history are not provided, so phenotype specificity cannot be judged.
PP5 Met Met: ClinVar records the exact variant as Pathogenic from the CFTR2 expert panel, meeting the instructed PP5 source requirement.
clinvar
BA1 Not met Not met: gnomAD v4.1 maximum frequency is 0.000510097, far below the >=0.05 BA1 threshold.
gnomad_v2 gnomad_v4
BS1 Not met Not met: the highest gnomAD v4.1 frequency is 0.000510097, below the generic >=0.01 BS1 default.
gnomad_v2 gnomad_v4
BS2 Not met Not met: gnomAD v4.1 reports 0 homozygotes among 1,609,586 alleles, so no healthy adult homozygote is observed.
gnomad_v2 gnomad_v4
BS3 Not met Not met: G551D baseline chloride transport was approximately 1.0% of normal in an independent FRT-cell assay, demonstrating rather than excluding damaging CFTR dysfunction.
PMID:17353351 PMID:19846789 PMID:22293084
BS4 Not assessed Not assessed: no informative affected relatives are documented as lacking the variant, so lack of segregation cannot be evaluated.
BP1 Not met Not met: recurrent pathogenic missense CFTR variant G551D with severe gating dysfunction contradicts a primarily truncating-only disease mechanism.
PMID:2236053 PMID:17353351 PMID:1379413
BP2 Not met Not met: the documented G551D/delta F508 relationship is trans in recessive CFTR, not cis or trans in a fully penetrant dominant disorder.
PMID:1379413
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: missense REVEL score 0.99 exceeds the BP4 supporting threshold of <= 0.29.
revel
BP5 Not assessed Not assessed: no case-level report establishes an alternate molecular basis for disease in a patient carrying this variant.
BP6 Not met Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification was identified for NM_000492.4:c.1652G>A.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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