Variant classification summary

NM_000492.4:c.350G>A

CFTR · NP_000483.3:p.(Arg117His) · NM_000492.4

GRCh37: chr7:117171029 G>A · GRCh38: chr7:117530975 G>A

Gene: CFTR Transcript: NM_000492.4

Final call

VUS

PM3 moderate PP3 moderate PP5 supporting

Variant details

Gene

CFTR

Transcript

NM_000492.4

Protein

NP_000483.3:p.(Arg117His)

gnomAD AF

0.0021350120911715234 (v4.1)

ClinVar

drug response

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM3 moderate: R117H was observed in an affected CBAVD patient in trans with a complete CFTR-gene deletion.

2

PP3 moderate: REVEL 0.807 meets the adjudicated moderate threshold of 0.773 or higher.

3

PP5 supporting: the exact CFTR2 ClinVar expert-panel record classifies R117H as Pathogenic.

Final determination: Under the generic ACMG/AMP 2015 fallback, two moderate criteria plus one supporting criterion do not satisfy a pathogenic or likely pathogenic rule, and no benign rule is satisfied, resulting in VUS.

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 met	Not met: only c.350G>A is documented for p.Arg117His, with no distinct nucleotide change producing the same amino-acid substitution.	clinvar PMID:17329263
PS2	Not assessed	Not assessed: the variant was reported in 25 alleles, but confirmed maternity, paternity, de novo status, and absence of family history were not documented.	PMID:17329263
PS3	Not assessed	Not assessed: R117H is linked to reduced conductance only by an unverified lead, without auditable controls, replication, quantitative results, or diagnostic-laboratory validation.
PS4	Not assessed	Not assessed: R117H was reported in 25 of 390 CBAVD alleles, but no matched control count or complete case frequency permits the required OR >5.0 and 95% CI excluding 1.0.	PMID:17329263 gnomad_v4
PM1	Not assessed	Not assessed: Cancer Hotspots found no significant CFTR R117 hotspot, and no supplied source establishes residue 117 as a critical domain without benign variation.	hotspots cosmic PMID:18567645
PM2	Not met	Not met: gnomAD v4.1 AF is 0.00213501, exceeding the supplied PM2 threshold of 0.0001 despite the variant being uncommon.	gnomad_v4 gnomad_v2 generic_acmg_combination_rules
PM3	Met	Met: one affected CBAVD patient had R117H in trans with a maternally inherited complete CFTR-gene deletion, providing direct phase evidence.	PMID:17329263
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 verified pathogenic alternate missense change at Arg117 is available in the supplied comparator evidence.	pm5_candidates PMID:17329263
PM6	Not assessed	Not assessed: cohort detection of 25 R117H alleles does not document an assumed de novo event or parental absence of the variant.	PMID:17329263
PP1	Not assessed	Not assessed: 25 R117H alleles were reported in unrelated patients, but no multiple affected relatives or informative meioses were documented.	PMID:17329263
PP2	Not assessed	Not assessed: the supplied evidence does not establish both low benign missense variation and a common CFTR missense disease mechanism at gene level.	PMID:17329263 clinvar
PP3	Met	Met at moderate strength: missense REVEL 0.807 meets the generic PP3 moderate threshold of >=0.773.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history is supplied to determine whether the presentation is highly specific for a single CFTR-related disease.
PP5	Met	Met: the exact-variant ClinVar expert-panel record from CFTR2 classifies R117H as Pathogenic, satisfying the specified PP5 evidence path.	clinvar PMID:23974870
BA1	Not assessed	Not assessed: gnomAD v4.1 grpmax FAF is 0.00263119, below the 0.05 BA1 threshold, while ClinVar shows a pathogenic low-penetrance disease association.	gnomad_v4 gnomad_v2 clinvar
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00263119, below the generic 0.01 BS1 threshold for an allele frequency greater than expected for disease.	gnomad_v4 gnomad_v2 generic_acmg_combination_rules
BS2	Not assessed	Not assessed: gnomAD reports 6 v4.1 homozygotes but does not establish healthy adult status, phenotype, age, or full early-age penetrance.	gnomad_v4 gnomad_v2 clinvar
BS3	Not assessed	Not assessed: no auditable variant-specific study demonstrates that R117H has no damaging effect on CFTR function or splicing.
BS4	Not assessed	Not assessed: no affected relatives with negative testing were reported, so lack of segregation cannot be established.	PMID:17329263
BP1	Not assessed	Not assessed: no supplied gene-level evidence determines whether CFTR disease is caused primarily by truncating rather than missense variants.	PMID:17329263 clinvar
BP2	Not met	Not met: R117H was observed with IVS8(T)5 in cis, but the study states IVS8(T)5 was not considered CF-causing and therefore not pathogenic for BP2.	PMID:17329263
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 0.807 exceeds the generic BP4 supporting cutoff of <=0.29.	revel
BP5	Not assessed	Not assessed: no case-level alternate molecular diagnosis is documented for an individual carrying CFTR R117H.
BP6	Not assessed	Not assessed: no exact-variant ClinVar expert-panel Benign or Likely benign classification is documented for R117H.	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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