The CFTR NM_000492.4:c.1652G>A (NP_000483.3:p.(Gly551Asp)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: G551D showed approximately 120-fold lower channel open probability than wild type and concordant chloride-transport defects across independent cellular assays. Based on available guidelines, this variant is considered to be Pathogenic. This variant is considered to be drug response by the VCEP (ClinPGx; ClinVar ID 7120).
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.CFTR encodes an ATP-binding cassette family protein that functions as a chloride channel, helping regulate salt and water movement across epithelial tissues. Disruption of CFTR causes cystic fibrosis, an inherited disorder affecting the lungs, digestive system, and other organs; CFTR has no established primary role in cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
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.
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.
Met at supporting strength: 79 affected individuals were G551D/delta F508 compound heterozygotes, establishing G551D in trans with pathogenic F508del.
Met, strong: missense REVEL score 0.99 exceeds the generic PP3 strong threshold of 0.932.
Met: ClinVar records the exact variant as Pathogenic from the CFTR2 expert panel, meeting the instructed PP5 source requirement.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PS3 strong and PP3 strong satisfy the generic ACMG two-strong rule, with additional PM1 moderate, PM3 supporting, and PP5 supporting evidence.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 631 / 1,609,586 alleles. Recorded AF 0.000392026. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000180696; MAF= 0.01807%, 51/282242 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000396006; MAF= 0.03960%, 51/128786 alleles, homozygotes = 0); grpmax FAF= 0.00029647.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001628841350852427, 3/18418 alleles, homozygotes = 0).
Recorded REVEL score: 0.990. Refer to the recorded PP3/BP4 rationale for interpretation.
27 Pathogenic · 1 pathogenic. ClinVar API review status: practice guideline.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 9 not met · 10 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PS4 was not assessed because the available case-frequency reports produce a strongly positive exploratory OR, but ancestry-matched case-control evidence and sufficiently characterized denominators are lacking.
PP4 and BP5 were not assessed because patient-level phenotype/family-history data and an alternate molecular basis, respectively, are not documented.
PP5 was met at supporting strength from the exact-variant ClinVar CFTR2 expert-panel Pathogenic classification; BP6 was not met because no qualifying expert-panel benign classification was identified.
Allelic evidence supports PM3 because G551D was reported in trans with pathogenic F508del in affected CF compound heterozygotes; the same observation does not satisfy BP2.
The variant is missense, so PP3 and BP4 use the REVEL path exclusively; the available SpliceAI result is not counted for either criterion.
REVEL 0.99 supports PP3 at strong strength and does not support BP4 at any supplied strength.
No criteria match.
PS3 is met at strong strength. The exact G551D variant was evaluated in multiple concordant, biologically relevant CFTR functional systems with appropriate wild-type and disease-relevant comparisons. Bompadre et al. used CHO-cell expression, Western blotting, whole-cell patch clamp, and excised inside-out single-channel electrophysiology; G551D trafficked comparably to wild type but had markedly impaired ATP-dependent gating, with estimated open probability approximately 0.0037 at 1 mM ATP, about 120-fold below wild type. Van Goor et al. reproduced impaired G551D function in recombinant FRT cells and primary human bronchial epithelial cultures, with VX-770 increasing G551D channel open probability approximately sixfold and CFTR-mediated chloride secretion approximately tenfold, from about 5% to approximately 48-50% of non-CF control. Jardašová et al. independently measured baseline G551D channel open probability of 0.019 +/- 0.01, approximately 5% of normal, and baseline chloride transport of 1.0 +/- 0.5% of normal in FRT cells; ivacaftor increased open probability to 0.121 +/- 0.035 and chloride transport to 55.3 +/- 6.3% of normal. These orthogonal electrophysiologic, epithelial transport, and airway-cell assays establish a damaging CFTR gating defect and are substantially stronger than a single nonvalidated assay. The studies are not presented as a validated clinical diagnostic laboratory assay, so the evidence is calibrated as strong rather than very strong.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
p.Gly551Asp lies at residue 551 in the first CFTR nucleotide-binding fold, a well-established ATP-associated functional domain. PMID:2236053 places G551D within the first NBF and reports G551 as highly conserved among nucleotide-binding-fold proteins; PMID:1379413 likewise places G551D within the first nucleotide-binding fold. The case has no VCEP domain table, no hotspot route is needed, and no benign classification or benign functional evidence for this residue is supplied. The variant is rare in gnomAD v4.1 (AF 0.000392026; 631/1,609,586 alleles; no homozygotes), consistent with absence of common benign variation at the observed site.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
CFTR is an autosomal recessive disorder gene. Hamosh et al. studied 79 affected individuals explicitly described as compound heterozygotes for G551D and delta F508; compound heterozygosity establishes the G551D allele in trans with the pathogenic F508del allele in affected probands. This satisfies the generic PM3 definition at supporting strength.
For recessive disorders, detected in trans with a pathogenic variant...This requires testing of parents (or offspring) to determine phase.
The variant is a missense SNV, NM_000492.4:c.1652G>A (NP_000483.3:p.(G551D)); therefore the applicable generic computational path is REVEL only. The recorded REVEL score is 0.99, which meets the supplied generic ACMG/ClinGen-SVI PP3 strong threshold of >= 0.932. SpliceAI is not used for PP3 in this missense situation, and BayesDel is not used because no generic ACMG-strength calibration is established.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Expert panel CFTR2 classified as Pathogenic.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
PM2 is not met under the supplied generic SVI threshold. The variant is present in gnomAD v2.1 at AF 0.000180696 (51/282,242 alleles) and in gnomAD v4.1 at AF 0.000392026 (631/1,609,586 alleles); both exceed the supporting PM2 threshold of <=0.0001. The highest observed subpopulation frequencies are 0.000396006 in gnomAD v2.1 and 0.000510097 in gnomAD v4.1, with 0 homozygotes in both datasets. No VCEP requires a non-cancer or exome-only source for this gene, and no non-cancer subset result is present; default all-comers totals therefore govern.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
BA1 is not met. The highest observed allele frequency is 0.000510097 (0.05101%) in gnomAD v4.1 European (non-Finnish) individuals, and the overall gnomAD v4.1 frequency is 0.000392026 (0.03920%; 631/1,609,586 alleles), both far below the 0.05 stand-alone benign threshold. gnomAD v2.1 is also below the threshold at 0.000180696 (0.01807%; 51/282,242 alleles). No governing VCEP specifies an alternate population source, so the default all-comers gnomAD datasets apply; no non-cancer subset result is present in the case evidence.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met. The highest observed allele frequency is 0.000510097 (0.05101%) in gnomAD v4.1 European (non-Finnish) individuals, below the generic 0.01 default threshold, and the overall frequency is 0.000392026 (0.03920%). Cystic fibrosis is an early-onset autosomal-recessive disorder with substantial allelic heterogeneity; the available frequency is not greater than expected for the disorder. No reduced-penetrance or ancestry-founder exception is indicated, and no maximum-credible-frequency calculation is needed to reject the default BS1 path.
Allele frequency is greater than expected for disorder.
BS2 is not met. gnomAD v2.1 reports 0 homozygotes among 282,242 alleles and gnomAD v4.1 reports 0 homozygotes among 1,609,586 alleles; therefore the required observation of this recessive-disease allele in a healthy adult homozygote is absent. Heterozygous carrier observations alone do not satisfy the recessive BS2 definition.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
BS3 is not met. The relevant functional studies do not show no damaging effect; instead, they consistently show impaired CFTR gating and chloride transport for the exact G551D variant. In CHO cells, G551D open probability was approximately 0.0037 at 1 mM ATP, about 120-fold below wild type. Independent FRT-cell assays measured baseline open probability at approximately 5% of normal and baseline chloride transport at approximately 1.0 +/- 0.5% of normal. Primary human bronchial epithelial cultures carrying G551D/F508del also showed markedly reduced CFTR-mediated chloride secretion before potentiation. Therefore, the available functional evidence directly contradicts the BS3 direction; no benign functional result or validated normal-function assay for this variant was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BP1 does not apply because CFTR disease is not established as a gene for which primarily truncating variants are known to cause disease. The evidence documents a recurrent pathogenic missense variant, G551D, in the first nucleotide-binding fold, and functional studies demonstrate a severe gating defect; this is direct evidence that pathogenic missense variation is an important CFTR disease mechanism rather than a primarily truncating-only mechanism.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The relevant affected-proband observation is G551D/delta F508 compound heterozygosity, which supports trans phase in the autosomal recessive CFTR disorder. BP2 requires either trans phase in a fully penetrant dominant disorder or cis phase with a pathogenic variant; neither BP2 pathway is met here.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The variant is a missense SNV, so BP4 must be judged on the REVEL path only. The recorded REVEL score is 0.99, which does not meet any supplied BP4 threshold, including the strong threshold of <= 0.016, moderate threshold of <= 0.183, or supporting threshold of <= 0.29. The available SpliceAI max delta of 0.015 is not applicable to BP4 for a missense variant and is not substituted for the non-supportive REVEL result; BayesDel is not available for generic ACMG strength assignment.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
ClinVar Variation ID 7120 is an exact match for the variant and contains a Pathogenic expert-panel classification from CFTR2, but no exact-variant ClinVar expert-panel classification of Benign or Likely benign was identified. The available evidence therefore does not satisfy the instructed BP6 trigger.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is p.Gly551Asp, and the evidence establishes this amino-acid change as a known CFTR disease-associated change. However, PS1 requires a previously established pathogenic variant producing the same amino-acid change through a different nucleotide change; the available evidence does not identify an independent alternate nucleotide substitution for Gly551Asp. The exact c.1652G>A observation cannot serve as the required alternate nucleotide change.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
No case-level evidence documents a proband with cystic fibrosis, absence of family history, confirmed maternity, and confirmed paternity for NM_000492.4:c.1652G>A. The available evidence describes published G551D cohorts and functional studies but does not establish a de novo event or parental testing for this proband.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The literature packet contains variant-specific reports of G551D among affected cystic-fibrosis chromosomes, including 3 of 40 non-ΔF508 CF chromosomes in PMID:2236053 and a reported worldwide frequency of 3.1% among CF chromosomes in PMID:1379413. Using the 3/40 count against gnomAD v4.1 European (non-Finnish) controls (600/1,176,248 alleles), the exploratory allele-count OR is 158.87 with a Woolf 95% CI of 48.85–516.67; the explicit PS4 comparison is OR >5.0 and CI not including 1.0, so this numerical comparison is positive. However, the affected cohort ancestry is not sufficiently matched to the selected gnomAD control population, and the reported case series are not a clearly defined case-control study; therefore a validated PS4 assessment is not made. The literature_pass packet's ai_classified_papers contains no paper classified as PS4, and the listed PS4 candidates were not independently verified as case-control evidence in paper_extracts.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
The available PM5 comparator collection contains no same-residue candidates, and the supplied literature extracts do not establish a different pathogenic missense substitution at CFTR residue 551. The exact G551D variant itself cannot satisfy PM5.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
No case-level evidence documents an assumed de novo occurrence of NM_000492.4:c.1652G>A in a proband. The materials do not report parental genotypes, an unconfirmed de novo observation, or the relevant disease phenotype for a specific patient.
Assumed de novo, but without confirmation of paternity and maternity.
No family pedigree or individual-level segregation data are provided showing NM_000492.4:c.1652G>A co-segregating with cystic fibrosis in multiple affected family members. The available G551D literature reports cohorts and functional studies rather than a documented familial segregation series for this variant.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The evidence does not establish both PP2 requirements at the gene level: a low rate of benign missense variation and missense variants as a common disease mechanism. CFTR has documented pathogenic missense variants, including G551D, but the supplied material does not provide a gene-level benign-missense-rate assessment or a rule-supported comparison demonstrating the required mechanism.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The available evidence describes CFTR G551D in patients with cystic fibrosis and related research cohorts, but it does not provide the phenotype or family history of the individual being interpreted. Without patient-level clinical findings, the required judgment that the phenotype is highly specific for a disease with a single genetic etiology cannot be made.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
No family-level evidence identifies affected relatives who lack NM_000492.4:c.1652G>A. Without an informative pedigree, affected-member genotypes, and phenotype assessments, lack of segregation cannot be distinguished from absent family data or phenocopy and BS4 cannot be assessed.
Lack of segregation in affected members of a family.
No case-level evidence was identified showing that this variant occurred in a case with an alternate molecular basis for disease. The available CFTR literature documents affected individuals carrying G551D but does not establish an alternate molecular etiology for those cases.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000492.4:c.1652G>A in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Gly551Asp). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000492.4:c.1652G>A in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Gly551Asp). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000492.4:c.1652G>A in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Gly551Asp). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000492.4:c.1652G>A in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Gly551Asp). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in CFTR, mapped onto the exon structure of NM_000492.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)600 / 1,176,248 | 0.00051 |
| Remaining individuals25 / 62,310 | 0.0004 |
| African/African American6 / 74,798 | 8e-05 |
| European (non-Finnish)51 / 128,786 | 0.0004 |
This variant is present in gnomAD v4.1 (AF= 0.000392026; MAF= 0.03920%, 631/1609586 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000510097; MAF= 0.05101%, 600/1176248 alleles, homozygotes = 0); grpmax FAF= 0.00047604.
This variant is present in gnomAD v2.1 (AF= 0.000180696; MAF= 0.01807%, 51/282242 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000396006; MAF= 0.03960%, 51/128786 alleles, homozygotes = 0); grpmax FAF= 0.00029647.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001628841350852427, 3/18418 alleles, homozygotes = 0).
The variant is a missense SNV, NM_000492.4:c.1652G>A (NP_000483.3:p.(G551D)); therefore the applicable generic computational path is REVEL only. The recorded REVEL score is 0.99, which meets the supplied generic ACMG/ClinGen-SVI PP3 strong threshold of >= 0.932. SpliceAI is not used for PP3 in this missense situation, and BayesDel is not used because no generic ACMG-strength calibration is established.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The variant is a missense SNV, so BP4 must be judged on the REVEL path only. The recorded REVEL score is 0.99, which does not meet any supplied BP4 threshold, including the strong threshold of <= 0.016, moderate threshold of <= 0.183, or supporting threshold of <= 0.29. The available SpliceAI max delta of 0.015 is not applicable to BP4 for a missense variant and is not substituted for the non-supportive REVEL result; BayesDel is not available for generic ACMG strength assignment.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000492.4:c.1652G>A in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Gly551Asp). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.99. BayesDel score = 0.584218.
9 paper records listed. 6 cited in the classification.
The glycine-to-aspartic acid missense mutation at codon 551 (G551D), which is within the first nucleotide-binding fold of the cystic fibrosis transmembrane conductance regulator (CFTR), is the third most common cystic fibrosis (CF) mutation, with a worldwide frequency of 3.1% among CF chromosomes.
Location Abstract
Context Clinical comparison of CF patients carrying G551D and ΔF508 alleles, including individuals with both mutations and assessment of clinical features such as meconium ileus.
The G551D mutation completely abolishes the response of the channel to ATP and ADP
Location Introduction; Results, “Expression of G551D-CFTR and G1349D-CFTR” and “ATP-dependent Gating of G551D-CFTR and G1349D-CFTR”
Context WT, G551D, and G1349D CFTR were expressed in CHO cells and evaluated by Western blotting, whole-cell patch-clamp recordings, and excised inside-out membrane-patch single-channel electrophysiology with ATP, ADP, and AMP-PNP.
In recombinant cells VX-770 increased CFTR channel open probability (Po) in both the F508del processing mutation and the G551D gating mutation. VX-770 also increased Cl− secretion in cultured human CF bronchial epithelia (HBE) carrying the G551D gating mutation on one allele and the F508del processing mutation on the other allele by ∼10-fold, to ∼50% of that observed in HBE isolated from individuals without CF.
Location Abstract; Results, “Pharmacological Characterization of VX-770” and “Effect of VX-770 in Primary Cultures of HBE Carrying G551D and F508del CFTR Mutations”
Context Recombinant FRT cells expressing human G551D CFTR; excised inside-out membrane patch recordings; primary air-interface human bronchial epithelial cultures from a CF donor carrying G551D/F508del; Ussing-chamber measurements of transepithelial current and open-circuit potential, plus airway-surface-liquid volume and cilia-beat-frequency assays.
Subjects had to be 18 years of age or older and have cystic fibrosis,9 a G551D mutation on at least one CFTR allele, and a forced expiratory volume in 1 second (FEV1) of 40% or more of the predicted value for age, sex, and height.10
Location Methods, Subjects eligibility criteria
Context Randomized, double-blind, placebo-controlled, multicenter phase 2 trial of oral VX-770 in adults with cystic fibrosis and a G551D mutation on at least one CFTR allele; CFTR function was assessed by nasal potential difference and sweat chloride concentration, with FEV1 as a clinical outcome.
Acute (5 min) addition of 10 μM ivacaftor increased the channel open probability of all CFTR gating mutations tested, reaching levels equivalent to 30% to 118% of normal CFTR.
Location Results, sections 2.1–2.3; Table 1; Table 2
Context In vitro studies in engineered Fischer rat thyroid (FRT) cells expressing G551D-CFTR; inside-out patch-clamp electrophysiology measured channel open probability, and Ussing chamber assays measured forskolin-stimulated chloride transport. Ivacaftor was tested acutely at 10 μM; n=3-5 for patch-clamp measurements and n=4-6 for chloride-transport measurements.
Five of the missense mutations (A455E, S5491, S549R, G551D, R560T) occurred at highly conserved amino acid residues in the first NBF.
Location Table 3; Results and Discussion, paragraphs describing mutation frequencies, DNA marker haplotypes, and clinical phenotype
Context CF families included 46 Canadian families plus additional Israeli families; direct sequencing surveyed exons 9–12, 19–23, and exon 13 in 29 individuals carrying 40 non-ΔF508 CF chromosomes, with mutation-specific detection including ASO hybridization.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.000392026; MAF= 0.03920%, 631/1609586 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000510097; MAF= 0.05101%, 600/1176248 alleles, homozygotes = 0); grpmax FAF= 0.00047604.
This variant is present in gnomAD v2.1 (AF= 0.000180696; MAF= 0.01807%, 51/282242 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000396006; MAF= 0.03960%, 51/128786 alleles, homozygotes = 0); grpmax FAF= 0.00029647.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001628841350852427, 3/18418 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Pathogenic (27 clinical laboratories) and as pathogenic (1 clinical laboratory) and as drug response by ClinPGx (expert panel) and as Pathogenic by CFTR2 (expert panel). (ClinVarID = 7120)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.99. BayesDel score = 0.584218.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.