The CFTR NM_000492.4:c.1521_1523del (NP_000483.3:p.(Phe508del)) in-frame deletion variant has previously been reported in somatic cancers (COSMIC; COSV50043929, n = 2 times). Experimental evidence: F508del-CFTR showed approximately 3% of wild-type chloride-channel activity with defective processing and markedly reduced cell-surface delivery. Based on available guidelines, this variant is considered to be Likely Pathogenic. This variant is considered to be Pathogenic by the VCEP (CFTR2; ClinVar ID 7105).
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely 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 (strong): F508del-CFTR showed approximately 3% of wild-type chloride-channel activity with defective processing and markedly reduced cell-surface delivery.
Met, supporting: affected twins were homozygous for F508del, demonstrating the variant on both alleles in this recessive CFTR disorder.
Met: the three-nucleotide in-frame deletion removes one amino acid, p.Phe508del, in the functional CFTR NBD1 domain and is not reported as a repeat-region variant.
Met: ClinVar's exact CFTR p.Phe508del record has a Pathogenic classification from the CFTR2 expert panel.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS3 strong, PM4 moderate, PM3 supporting, and PP5 supporting satisfy the generic ACMG/AMP combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 19,237 / 1,612,320 alleles. Recorded AF 0.0119313. Recorded homozygote count 58.
This variant is present in gnomAD v2.1 (AF= 0.00717192; MAF= 0.71719%, 2027/282630 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0123843; MAF= 1.23843%, 1598/129034 alleles, homozygotes = 1); grpmax FAF= 0.0117528.
This variant is present in gnomAD-Canada v1.0 (AF= 0.009338690411553914, 172/18418 alleles, homozygotes = 2).
Recorded SpliceAI maximum delta score: 0.007. Refer to the recorded PP3/BP4 rationale for interpretation.
77 Pathogenic · 3 pathogenic · 1 Likely pathogenic. ClinVar API review status: practice guideline.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV50043929, n = 2 times).
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: 4 met · 4 not met · 10 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Only the five requested criteria were adjudicated.
No VCEP covers CFTR in this case, so generic ACMG/AMP rules govern.
PP5 is met solely from the exact-variant CFTR2 expert-panel pathogenic ClinVar assertion; ordinary laboratory submissions, aggregate labels, and non-expert assertions were excluded.
BA1 is not met because the maximum observed allele frequency is 0.0149425, below the 0.05 stand-alone threshold.
BS1 is not assessed because the frequency exceeds the generic 1% default but the disease-specific prevalence, penetrance, allelic heterogeneity, and founder-allele inputs needed to determine whether it is greater than expected are unavailable.
BS2 is not assessed because population homozygote counts do not document healthy adult status or absence of early-onset cystic fibrosis.
PM2 is not met because the variant is repeatedly present at frequencies far above the <=0.0001 supporting threshold.
No criteria match.
PS3 is met at strong strength. The variant is the CFTR ΔF508/F508del deletion. In recombinant CFTR expression experiments, the F508del construct was directly compared with wild-type and other CFTR mutants using cell-surface immunofluorescence, immunoblotting, iodide-efflux assays, and whole-cell electrophysiology. The study reported defective processing, markedly reduced plasma-membrane delivery, and residual chloride-channel activity of approximately 3% of wild-type activity. These orthogonal functional readouts and explicit wild-type comparison provide well-established evidence of a damaging effect on CFTR protein function; however, the evidence is not described as validated and reproducible in a clinical diagnostic laboratory setting, so no escalation beyond the standard strong PS3 level is applied.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
CFTR-related cystic fibrosis is recessive. Affected monozygotic twins were reported as homozygous for the F508del variant after PCR testing of blood-derived DNA, demonstrating the variant on both homologous alleles; therefore the assessed allele is present in trans with a pathogenic F508del allele in affected individuals. A separate affected child was reported with the biallelic genotype p.Phe508del/p.Gly970Asp, but that report does not establish parental phase, so it is not used as independent phase evidence. The homozygous affected-twin observation supports PM3 at supporting strength.
For recessive disorders, detected in trans with a pathogenic variant...Note: This requires testing of parents (or offspring) to determine phase.
NM_000492.4:c.1521_1523del is an in-frame three-nucleotide deletion in the MANE/RefSeq CFTR transcript, producing the one-amino-acid protein deletion NP_000483.3:p.(Phe508del) in exon 11. The affected residue lies in CFTR NBD1, a characterized functional domain, and the available variant annotation identifies an in-frame deletion rather than a frameshift or splice-site change. No evidence places this deletion in a repetitive region; therefore it satisfies the generic PM4 definition for a protein-length change caused by an in-frame deletion in a non-repeat region. The PM4 code is applied at its standard moderate strength.
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
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. The generic ClinGen SVI threshold supplied for PM2 Supporting is <=0.0001. The variant is present well above that threshold in every relevant population dataset: gnomAD v2.1 all-comers AF 0.00717192, gnomAD v2.1 non-cancer exomes AF 0.00678844, gnomAD v3.1 non-cancer genomes AF 0.0077383, and gnomAD v4.1 all-comers AF 0.0119313. Because the variant is observed repeatedly in controls and is not at an extremely low frequency for a recessive condition, PM2 is not met.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BA1 is not met. The generic ACMG/AMP stand-alone threshold supplied for BA1 is >=0.05. The variant's all-comers gnomAD v4.1 allele frequency is 0.0119313 (19,237/1,612,320 alleles), and the highest reported population frequency is 0.0149425 in European (non-Finnish) individuals; the gnomAD v2.1 all-comers frequency is 0.00717192 (2,027/282,630 alleles). The available non-cancer subsets are also below 0.05: gnomAD v2.1 non-cancer exomes AF 0.00678844 and gnomAD v3.1 non-cancer genomes AF 0.0077383. None reaches the 5% stand-alone threshold.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS3 is not met. The available variant-specific functional evidence does not show no damaging effect on CFTR protein function or splicing; instead, the experimental results show defective processing, reduced cell-surface expression, and approximately 3% of wild-type chloride-channel activity. No independent well-established assay demonstrating preserved CFTR function or normal splicing was identified for this variant.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The governing rule requires a reputable-source benign report, and the generic BP6 trigger is limited to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar instead records the exact p.Phe508del variant as Pathogenic from the CFTR2 expert panel; no exact-variant Benign or Likely benign expert-panel assertion is present. BP6 is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No case-specific proband phenotype, parental genotypes, or confirmed maternity and paternity evidence is provided. Therefore, de novo occurrence cannot be assessed under PS2.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The governing ACMG/AMP rule requires a case-control comparison with RR or OR >5.0 and a confidence interval excluding 1.0. PMID:23974870 reports p.Phe508del in 70% of identified CFTR alleles among 39,696 affected individuals, but the extracted report does not provide a variant-specific unaffected/control count or a case prevalence denominator suitable for computing an OR and 95% CI. gnomAD v4.1 reports the variant at AF 0.0119313 (19,237/1,612,320 alleles), but comparing this allele frequency with the CFTR2 allele share would not be a valid case-control OR without compatible case and control denominators. The literature_pass PS4 leads were checked: PMID:18197057 explicitly lacks variant-specific F508del findings, and no verified extracted evidence for the indexed PMID:25431289 or PMID:29506920 supplies the required counts. Therefore PS4 cannot be assessed from the available evidence.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... 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.
No case-specific evidence shows that CFTR c.1521_1523del arose de novo in the proband, with or without parental testing. Therefore, PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, informative meioses, or variant-disease co-segregation data are reported for this case. Therefore, PP1 cannot be assessed.
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 governing rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The available case evidence identifies the variant as CFTR p.(Phe508del) and includes published CF cases, but it does not provide this patient's phenotype or family history and therefore does not establish that the patient's presentation is highly specific for cystic fibrosis. PP4 cannot be assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS1 is not assessed. The variant exceeds the generic 1% default in gnomAD v4.1 overall (AF 0.0119313) and in the European (non-Finnish) population (AF 0.0149425), and the gnomAD v2.1 non-cancer exome AF is 0.00678844. However, the governing rule defines BS1 as a frequency greater than expected for the disorder, and the supplied generic default must not be used alone when disease prevalence, penetrance, allelic heterogeneity, or a founder allele may explain the frequency. CFTR-related cystic fibrosis is recessive and F508del is a common founder allele, but this case does not provide the prevalence, penetrance, or disease-allele heterogeneity inputs needed for a maximum-credible-allele-frequency calculation under Whiffin et al. 2017 (PMID:28518168). Therefore the observed frequency cannot be adjudicated as greater than expected rather than expected for this disorder.
BS2 is not assessed. The variant is observed in homozygous individuals in population data: one homozygote in gnomAD v2.1, one in gnomAD v2.1 non-cancer exomes, one in gnomAD v3.1 non-cancer genomes, and 58 in gnomAD v4.1. These records do not establish that the individuals were healthy adults, do not provide their ages or clinical phenotypes, and do not demonstrate absence of cystic fibrosis despite the criterion's requirement for an observed healthy adult in a recessive disorder with full early-age penetrance expected. Population homozygote counts alone therefore cannot be converted into BS2.
No affected relatives have been evaluated for presence or absence of CFTR c.1521_1523del, and no family-level non-segregation evidence is provided. Therefore, BS4 cannot be assessed.
Lack of segregation in affected members of a family. ... Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals.
CFTR-related cystic fibrosis is recessive, so the BP2 trans-with-a-pathogenic-variant path for a fully penetrant dominant gene or disorder does not apply. No source reviewed provides a confirmed cis observation of F508del with another pathogenic CFTR variant. BP2 therefore cannot be assessed from the available allelic evidence.
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 governing rule requires the variant to be found in a case with an alternate molecular basis for disease. The available evidence includes CFTR-related case reports and population data but does not document an alternate molecular diagnosis in the interpreted case. BP5 cannot be assessed.
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.1521_1523del in CFTR is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_000483.3:p.(Phe508del). 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
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000492.4:c.1521_1523del in CFTR is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_000483.3:p.(Phe508del). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PS1 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_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000492.4:c.1521_1523del in CFTR is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_000483.3:p.(Phe508del). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM1 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_missense
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000492.4:c.1521_1523del in CFTR is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_000483.3:p.(Phe508del). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM5 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_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000492.4:c.1521_1523del in CFTR is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_000483.3:p.(Phe508del). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PP2 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_missense
PP3 is not applicable because this CFTR variant is an in-frame deletion, NM_000492.4:c.1521_1523del (NP_000483.3:p.(Phe508del)), rather than a missense or intronic, synonymous, or splice-region variant covered by the generic computational-evidence paths. The criterion is therefore outside scope before any predictor score is considered.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000492.4:c.1521_1523del in CFTR is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_000483.3:p.(Phe508del). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP1 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_missense
Although NM_000492.4:c.1521_1523del is an in-frame deletion, the available evidence places p.Phe508del in the characterized CFTR NBD1 functional domain, not in a repetitive region without a known function. The variant therefore lies outside the variant location/context named by BP3 and BP3 is not applicable.
In frame-deletions/insertions in a repetitive region without a known function.
BP4 is not applicable because this CFTR variant is an in-frame deletion, NM_000492.4:c.1521_1523del (NP_000483.3:p.(Phe508del)), rather than a missense or intronic, synonymous, or splice-region variant covered by the generic computational-evidence paths. A no-impact splice prediction cannot establish no impact on the gene product for an in-frame protein-length-changing variant, so the criterion is outside scope before any predictor score is considered.
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.1521_1523del in CFTR is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_000483.3:p.(Phe508del). 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)17610 / 1,178,514 | 0.01549 hom |
| Remaining individuals625 / 62,454 | 0.016 hom |
| Ashkenazi Jewish179 / 29,584 | 0.0061 |
| Admixed American234 / 60,008 | 0.00391 hom |
| European (Finnish)163 / 63,934 | 0.00251 hom |
| South Asian228 / 91,054 | 0.0025 |
| African/African American185 / 75,000 | 0.00251 hom |
| Middle Eastern11 / 6,058 | 0.0018 |
| Amish1 / 912 | 0.0011 |
| East Asian1 / 44,802 | 2.2e-05 |
| European (non-Finnish)1598 / 129,034 | 0.0121 hom |
| Remaining individuals49 / 7,214 | 0.0068 |
| Ashkenazi Jewish58 / 10,368 | 0.0056 |
| Admixed American135 / 35,426 | 0.0038 |
| African/African American65 / 24,958 | 0.0026 |
| European (Finnish)61 / 25,074 | 0.0024 |
| South Asian61 / 30,608 | 0.002 |
This variant is present in gnomAD v4.1 (AF= 0.0119313; MAF= 1.19313%, 19237/1612320 alleles, homozygotes = 58) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0149425; MAF= 1.49425%, 17610/1178514 alleles, homozygotes = 49); grpmax FAF= 0.0147572.
This variant is present in gnomAD v2.1 (AF= 0.00717192; MAF= 0.71719%, 2027/282630 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0123843; MAF= 1.23843%, 1598/129034 alleles, homozygotes = 1); grpmax FAF= 0.0117528.
This variant is present in gnomAD-Canada v1.0 (AF= 0.009338690411553914, 172/18418 alleles, homozygotes = 2).
PP3 is not applicable because this CFTR variant is an in-frame deletion, NM_000492.4:c.1521_1523del (NP_000483.3:p.(Phe508del)), rather than a missense or intronic, synonymous, or splice-region variant covered by the generic computational-evidence paths. The criterion is therefore outside scope before any predictor score is considered.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP4 is not applicable because this CFTR variant is an in-frame deletion, NM_000492.4:c.1521_1523del (NP_000483.3:p.(Phe508del)), rather than a missense or intronic, synonymous, or splice-region variant covered by the generic computational-evidence paths. A no-impact splice prediction cannot establish no impact on the gene product for an in-frame protein-length-changing variant, so the criterion is outside scope before any predictor score is considered.
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.1521_1523del in CFTR is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_000483.3:p.(Phe508del). 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).
9 paper records listed. 4 cited in the classification.
Also noteworthy is a shift (*15 Å) of the F508-containing helix within NBD1, associated with a correlated movement of ICL4 [Fig. 4; Online Resource 6(C)].
Location Results, ‘Model of the open form of the CFTR channel, generated by molecular dynamics,’ paragraph discussing conformer 1; related background in the Introduction
Context Sav1866-based CFTR homology modeling followed by unrestrained molecular-dynamics simulations of the MSD:NBD assembly in a hydrated POPC lipid bilayer at 310 K; the model excluded the R domain.
encontrándose en ambos hermanos la mutación homocigótica ΔF508.
Location Case report, molecular analysis; Discussion and Conclusions
Context Case report of two preterm monozygotic twins; genomic DNA from blood was analyzed by PCR using variant-specific primers.
We report the case of a 4 years and 6 months Caucasian child diagnosed with CF by positive newborn screening (blood immunoreactive trypsinogen 205 ng/ml, genotype: p.Phe508del/p.Gly970Asp, sweat chloride [SC]: 92–112 mEq/L).
Location Introduction, paragraph 2; Case Report, paragraph 1; Discussion, paragraphs 1–2
Context Single-patient case report involving ex vivo testing of nasal epithelial cells followed by lumacaftor/ivacaftor treatment and clinical follow-up with sweat chloride, lung clearance index, and fecal pancreatic elastase measurements.
Deletion of phenylalanine at position 508 (AF508), in the first nucleotide binding domain, is the most common CF-associated mutation, which accounts for 68% of CF chromosomes in caucasian populations (Kerem et al., 1989). AF508 has initially been associated with defective protein processing in vitro (Cheng et al., 1990) as well as in vivo (Denning et al., 1992; Kartner et al., 1992; Puchelle et al., 1993). However, when AF508 CFTR was expressed in cultured Vero cells (Dalemans et al., 1991), residual Cl- channel activity equal to ~3% of the activity observed after expression of the wild type CFTR was recorded, suggesting that under these conditions a small amount of AF508-CFTR is correctly processed to the cell membrane.
Location Introduction, paragraph 3; Results, ‘Immunolocalization of P574H-CFTR and other CFTR mutant proteins,’ paragraph 3; Discussion, paragraph 3
Context Recombinant vaccinia-virus expression of CFTR constructs in Vero and Chang cells; CFTR cell-surface immunofluorescence, Western blotting, iodide-efflux assays, and whole-cell electrophysiology, with AF508 compared against wild-type CFTR and other CFTR mutants.
The most common variant, p.Phe508del, accounted for 70% of the identified alleles in these patients.
Results, section '159 CFTR variants represent 96% of cystic fibrosis alleles,' paragraph 1
We recommend that carrier screening for cystic fibrosis, Canavan disease, familial dysautonomia, and Tay-Sachs disease be offered to all Ashkenazi Jews who are pregnant or considering pregnancy, according to current American College of Medical Genetics and/or the American College of Obstetricians and Gynecologists (ACOG) guidelines.
Recommendations, item 1
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= 0.0119313; MAF= 1.19313%, 19237/1612320 alleles, homozygotes = 58) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0149425; MAF= 1.49425%, 17610/1178514 alleles, homozygotes = 49); grpmax FAF= 0.0147572.
This variant is present in gnomAD v2.1 (AF= 0.00717192; MAF= 0.71719%, 2027/282630 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0123843; MAF= 1.23843%, 1598/129034 alleles, homozygotes = 1); grpmax FAF= 0.0117528.
This variant is present in gnomAD-Canada v1.0 (AF= 0.009338690411553914, 172/18418 alleles, homozygotes = 2).
This variant has been reported in ClinVar as Pathogenic (77 clinical laboratories) and as pathogenic (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by CFTR2 (expert panel) and as drug response by ClinPGx (expert panel). (ClinVarID = 7105)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV50043929, n = 2 times).
This variant does not lie in a statistically significant hotspot.