Variant NM_000492.4:c.3808G>A


Variant details:
Name NM_000492.4:c.3808G>A
Protein name NP_000483.3:p.(Asp1270Asn)
Genomic name (hg19) chr7:g.117282582G>A    UCSC    gnomAD
#Exon/intron exon 23
Legacy Name D1270N
Class disease-causing
Subclass CFTR-RD-causing
complex allele in 70.27% of patients associated with
  • c.220C>T - p.(Arg74Trp) : 100.00%
  • c.601G>A - p.(Val201Met) : 69.23%
    • WT sequence GAACACTGAAGGAGAAATCCAGATC G ATGGTGTGTCTTGGGATTCAATAAC
    Mutant sequence GAACACTGAAGGAGAAATCCAGATC A ATGGTGTGTCTTGGGATTCAATAAC


    External sources:
    dbSNP
    rs11971167


    Functional studies:


    Reference PMID Splicing mRNA level Maturation Localization Channel fonction (Cl-) Bicarbonate
    Mickle et al, 2000 10762539 ✓ ✓
    Van Goor et al, 2014 23891399 ✓ ✓ ✓
    Sosnay et al, 2013 23974870 ✓ ✓
    LaRusch et al, 2014 25033378 ✓ ✓ ✓


    « ✓ » 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
    IVA yesnoyesno
    TEZ-IVA yesnoyesno
    ELX-TEZ-IVA yesnoyesno


    clinical and functional data are provided by Vertex


    Pathogenicity predictions:
    AGVGD MAPP SIFT PPH2
    C15 0.00175 0 1
    VUS1 VUS5 VUS5 VUS5

    Color code:   non disease-causing <   VUS1 <   VUS2 <   VUS3 <   VUS4 <   VUS5 <   disease-causing




    2 individuals carrying this variant are reported in CFTR-NGS catalogue


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

    TOTAL NUMBER OF PATIENTS 74
    Asymptomatic compound heterozygote 7
    CF 4
    CFTR-RD50
    • Aquagenic palmoplantar keratoderma  1
    • Bronchiectasis  3
    • CBAVD  24
    • CRS-NP  2
    • Other  7
    • Pancreatitis  13
    Pending 5
    Pending (NBS) 8



    Detailed genotypes:
    Phenotype Patient ID Variant status Additional variants
    Other 3076heterozygoteCFTR-RD-causing - Cis
    CF-causing - Trans
    Other 4767heterozygoteCFTR-RD-causing - Cis
    CF-causing - Trans
    Other 5075heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Other 1124heterozygoteCFTR-RD-causing - Cis
    varying clinical consequence- Undef
    Other 4702heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Other 5383heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Other 3138homozygotec.220C>T - p.(Arg74Trp) - Trans
    c.3808G>A - p.(Asp1270Asn) - Trans
    c.601G>A - p.(Val201Met) - Trans
    Pending 3073heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Pending 4337heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Pending 4336heterozygoteCFTR-RD-causing - Cis
    CF-causing - Trans
    Pending 4078heterozygoteCFTR-RD-causing - Cis
    CF-causing- Undef
    Pending 4819heterozygoteCFTR-RD-causing- Undef
    CF-causing- Undef
    CBAVD 2347heterozygoteCFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    CBAVD 5875heterozygoteCFTR-RD-causing- Undef
    CF-causing- Undef
    CFTR-RD-causing- Undef
    CBAVD 5872heterozygoteCFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    CBAVD 3208heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing- Undef
    CBAVD 4556heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing- Undef
    CBAVD 4224heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    VUS2 - Trans
    CBAVD 3324heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    CBAVD 5866heterozygoteCFTR-RD-causing- Undef
    CF-causing- Undef
    CFTR-RD-causing- Undef
    CBAVD 5519heterozygoteCF-causing- Undef
    CFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    CBAVD 5223heterozygoteCF-causing- Undef
    CFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    CBAVD 892heterozygoteCFTR-RD-causing- Undef
    varying clinical consequence- Undef
    CFTR-RD-causing- Undef
    CBAVD 751heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    CBAVD 697heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    varying clinical consequence - Trans
    CBAVD 565heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    VUS4- Undef
    VUS1- Undef
    CBAVD 543heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    CBAVD 503heterozygoteCFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    CBAVD 4956heterozygotevarying clinical consequence- Undef
    CFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    CBAVD 1269heterozygoteCF-causing- Undef
    CFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    CBAVD 1294heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CFTR-RD-causing- Undef
    CBAVD 1366heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing- Undef
    CBAVD 1412heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    varying clinical consequence- Undef
    CBAVD 660homozygotec.220C>T - p.(Arg74Trp) - Trans
    c.3808G>A - p.(Asp1270Asn) - Trans
    c.601G>A - p.(Val201Met) - Trans
    CBAVD 1456homozygotec.220C>T - p.(Arg74Trp) - Trans
    c.3808G>A - p.(Asp1270Asn) - Trans
    c.601G>A - p.(Val201Met) - Trans
    CBAVD 507homozygotec.220C>T - p.(Arg74Trp) - Trans
    c.3808G>A - p.(Asp1270Asn) - Trans
    c.601G>A - p.(Val201Met) - Trans
    Asymptomatic compound heterozygote 2777heterozygoteCFTR-RD-causing - Cis
    CF-causing - Trans
    Asymptomatic compound heterozygote 3156heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Asymptomatic compound heterozygote 4517heterozygoteCFTR-RD-causing - Cis
    VUS1 - Trans
    Asymptomatic compound heterozygote 3794heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Asymptomatic compound heterozygote 314heterozygoteCFTR-RD-causing - Cis
    CF-causing - Trans
    Asymptomatic compound heterozygote 4989heterozygoteCFTR-RD-causing - Cis
    CF-causing - Trans
    Asymptomatic compound heterozygote 782homozygotec.220C>T - p.(Arg74Trp) - Trans
    c.3808G>A - p.(Asp1270Asn) - Trans
    c.601G>A - p.(Val201Met) - Trans
    CF 5993heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    CF 382heterozygoteVUS3 - Cis
    CFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    CF 5285heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    CF 5059heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Pending (NBS) 6090heterozygoteCF-causing- Undef
    CFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    Pending (NBS) 5996heterozygoteCF-causing- Undef
    Pending (NBS) 4593heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Pending (NBS) 5313heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Pending (NBS) 5853heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Pending (NBS) 991heterozygoteCFTR-RD-causing- Undef
    varying clinical consequence- Undef
    Pending (NBS) 5703heterozygoteVUS3 - Cis
    CFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Pending (NBS) 5446heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Aquagenic palmoplantar keratoderma 5470heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CFTR-RD-causing- Undef
    Pancreatitis 2302heterozygoteCFTR-RD-causing - Cis
    Pancreatitis 4894heterozygoteCFTR-RD-causing- Undef
    Pancreatitis 2538heterozygoteCFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    Pancreatitis 2327heterozygoteCFTR-RD-causing - Cis
    Pancreatitis 2242heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CFTR-RD-causing- Undef
    Pancreatitis 2137heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing- Undef
    Pancreatitis 2033heterozygoteCFTR-RD-causing - Cis
    CF-causing- Undef
    Pancreatitis 5623heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CFTR-RD-causing - Trans
    Pancreatitis 5620heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    Pancreatitis 3315heterozygoteCFTR-RD-causing - Cis
    VUS2 - Trans
    Pancreatitis 5869heterozygoteCFTR-RD-causing- Undef
    VUS3- Undef
    Pancreatitis 5741heterozygoteCF-causing- Undef
    Pancreatitis 5396heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    Bronchiectasis 5896heterozygoteCFTR-RD-causing - Cis
    VUS3- Undef
    Bronchiectasis 5897heterozygoteVUS3- Undef
    VUS1- Undef
    CFTR-RD-causing- Undef
    Bronchiectasis 5464heterozygoteCFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    CRS-NP 3143heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans
    CRS-NP 5994heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Cis
    CF-causing - Trans


    Color code:   non disease-causing <   VUS1 <   VUS2 <   VUS3 <   VUS4 <   VUS5 <   disease-causing



                CFTR variants are clustered into five groups:
    • 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.