Updates for c.221G>A:
2024-10-14 Class updated from VUS1 to non disease-causing
2024-12-09 Variant classified as non-disease-causing on the basis of epidemiological data (in particular high frequency in the general population), the number and type of diagnosis for patients reported in CFTR-France and functional data




Variant NM_000492.4:c.221G>A


Variant details:
Name NM_000492.4:c.221G>A
Protein name NP_000483.3:p.(Arg74Gln)
Genomic name (hg19)     chr7:g.117149144G>A    UCSC    
Genomic name (hg38) chr7:g.117509090G>A    UCSC
#Exon/intron exon 3
Legacy Name R74Q
Class non disease-causing
complex allele in 25.00% of patients associated with
  • c.890G>A - p.(Arg297Gln) : 100.00%
    • WT sequence AATCCTAAACTCATTAATGCCCTTC G GCGATGTTTTTTCTGGAGATTTATG
    Mutant sequence AATCCTAAACTCATTAATGCCCTTC A GCGATGTTTTTTCTGGAGATTTATG


    Effects of associated complex alleles:
    R297Q non disease-causing
    R74Q ; R297Q non disease-causing




    Other databases:
    dbSNP
    rs142540482



    Pathogenicity predictors:

    Functional studies:         +


    Reference PMID Splicing mRNA level Maturation Localization Channel fonction (Cl-) Bicarbonate
    LaRusch et al, 2014 25033378 ✓ ✓ ✓
    Bergougnoux et al, 2022 36567205 ✓ ✓ ✓ ✓ ✓


    « ✓ » indicates the type of analysis performed and not the results


    Response to modulators:         +


    Modulator FDA approval EMA approval in vitro / ex vivo data clinical data
    IVAnononono
    TEZ-IVA yesnoyesno
    ELX-TEZ-IVA yesnoyesno

    clinical and functional data presented above are provided by Vertex


    No patient found in CFTR-NGS catalogue


    4 patients carrying this variant are reported in CFTR-France:

    TOTAL NUMBER OF PATIENTS 4
    CFTR-RD3
    • CRS-NP  1
    • Pancreatitis  2
    Pending (NBS) 1




    Color code:   non disease-causing <   likely benign <   VUS <   likely pathogenic <   disease-causing

    Detailed genotypes:
    Phenotype Patient ID Variant status Additional variants
    Pancreatitis 3079heterozygote
    Pancreatitis 4618heterozygote
    Pending (NBS) 5312heterozygoteCF-causing - Trans
    CRS-NP 6158heterozygote


    Color code:   non disease-causing <   likely benign <   VUS <   likely pathogenic <   disease-causing



                CFTR variants are clustered into five groups (click here for more details about the classification of variants):
    • CF-causing: when in trans with another CF-causing mutation, will result in CF.
    • CFTR-RD causing: when in trans with a CF-causing mutation, will result in CFTR-related disorders (CFTR-RD) such as chronic pancreatitis, bronchiectasis, CRS-NP (chronic rhinosinusitis with or without nasal polyposis) or CBAVD (congenital absence of vas deferens), according to Bombieri C et al., 2011.
    • Varying clinical consequence: when in trans with another CF-causing mutation, can either result in CF or in a CFTR-RD.
    • Non disease-causing: when in trans with a CF-causing mutation, will not cause CF, nor CFTR-RD.
    • VUS (Variant of unknown clinical significance): unclassified because of insufficient data.



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