Variant NM_000492.4:c.1727G>C


Variant details:
Name NM_000492.4:c.1727G>C
Protein name NP_000483.3:p.(Gly576Ala)
Genomic name (hg19) chr7:g.117230454G>C    UCSC    
#Exon/intron exon 13
Legacy Name G576A
Class non disease-causing
Subclass NULL
complex allele in 69.70% of patients associated with
  • c.2002C>T - p.(Arg668Cys) : 98.91%
  • c.1327G>T - p.(Asp443Tyr) : 58.70%
    • WT sequence TTGTATTTATTAGACTCTCCTTTTG G ATACCTAGATGTTTTAACAGAAAAA
    Mutant sequence TTGTATTTATTAGACTCTCCTTTTG C ATACCTAGATGTTTTAACAGAAAAA


    Effects of associated complex alleles:
    R668C non disease-causing
    D443Y likely benign
    G576A ; R668C non disease-causing
    D443Y ; G576A ; R668C disease-causing - CFTR-RD-causing




    Other databases:
    dbSNP
    rs1800098



    Pathogenicity predictors:

    Functional studies:


    Reference PMID Splicing mRNA level Maturation Localization Channel fonction (Cl-) Bicarbonate
    Pagani et al, 2003 12719375 ✓
    El-Seedy et al, 2012 22678879 ✓ ✓ ✓
    Sosnay et al, 2013 23974870 ✓ ✓
    Bergougnoux et al, 2015 25797027 ✓ ✓ ✓


    « ✓ » 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


    No patient found in CFTR-NGS catalogue


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

    TOTAL NUMBER OF PATIENTS 132
    Asymptomatic compound heterozygote 17
    CF 6
    CFTR-RD99
    • Aquagenic palmoplantar keratoderma  3
    • Bronchiectasis  9
    • CBAVD  58
    • CRS-NP  2
    • Other  13
    • Pancreatitis  14
    Fetal bowel anomalies 1
    Pending 5
    Pending (NBS) 3
    Pending non-CF 1




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

    Detailed genotypes:
    Phenotype Patient ID Variant status Additional variants
    CF 4360heterozygoteCF-causing- Undef
    CF-causing- Undef
    CF 4665heterozygoteVUS3- Undef
    CF 5215heterozygoteCFTR-RD-causing- Undef
    VUS3- Undef
    CF 5053heterozygoteCF-causing- Undef
    VUS3- Undef
    CF 1128heterozygoteCF-causing - Cis
    varying clinical consequence - Trans
    CF 1559heterozygoteCF-causing- Undef
    CF-causing- Undef
    Other 4627heterozygoteCFTR-RD-causing - Trans
    Other 2433heterozygoteVUS3- Undef
    Other 4458heterozygoteCF-causing - Trans
    Other 4570heterozygoteVUS3 - Cis
    CF-causing - Trans
    Other 4809heterozygoteVUS3 - Cis
    CF-causing- Undef
    Other 4262heterozygoteCF-causing - Trans
    Other 4278heterozygoteVUS3 - Cis
    CF-causing - Trans
    VUS1- Undef
    Other 972heterozygoteCF-causing - Trans
    Other 5264heterozygoteVUS3- Undef
    CF-causing- Undef
    Other 5353heterozygoteCFTR-RD-causing- Undef
    Other 4671heterozygoteVUS3- Undef
    Other 5083heterozygoteVUS3- Undef
    CF-causing- Undef
    Other 5814heterozygoteVUS3- Undef
    CF-causing- Undef
    Fetal bowel anomalies 4672heterozygoteCFTR-RD-causing - Trans
    CBAVD 2989heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 3335heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 5590heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 5764heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 4752heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 4646heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 2853heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 2411heterozygote
    CBAVD 2485heterozygoteVUS3 - Cis
    CF-causing- Undef
    VUS3- Undef
    CBAVD 2551heterozygoteCF-causing- Undef
    CBAVD 2756heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 2806heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 2824heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 5610heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 4534heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 4571heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 4574heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 4612heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 4331heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 5943heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 5947heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 4279heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 549heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 556heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 658heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 659heterozygoteVUS3- Undef
    VUS3- Undef
    CBAVD 682heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 763heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 900heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 511heterozygoteVUS3 - Cis
    VUS3 - Trans
    CBAVD 508heterozygoteVUS3 - Cis
    CFTR-RD-causing - Trans
    CBAVD 497heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 4683heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 4722heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 4735heterozygoteVUS3 - Cis
    varying clinical consequence - Trans
    CBAVD 395heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 404heterozygoteVUS3 - Cis
    varying clinical consequence- Undef
    CBAVD 430heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 433heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 452heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 480heterozygoteVUS3- Undef
    CF-causing- Undef
    CBAVD 5463heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 5665heterozygoteVUS3 - Cis
    CFTR-RD-causing - Trans
    CBAVD 5882heterozygoteVUS3 - Cis
    CF-causing - Trans
    CBAVD 6223heterozygoteVUS3 - Cis
    varying clinical consequence- Undef
    VUS3- Undef
    CBAVD 2078heterozygoteCFTR-RD-causing- Undef
    CF-causing- Undef
    CBAVD 2141heterozygoteCF-causing- Undef
    CBAVD 1833heterozygoteCF-causing- Undef
    CBAVD 5181heterozygoteVUS3 - Cis
    CF-causing - Trans
    VUS3- Undef
    CBAVD 1248heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 1335heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 1340heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 1365heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 1381heterozygoteVUS3 - Cis
    CBAVD 1423heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 1510heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 1512heterozygoteVUS3 - Cis
    CF-causing- Undef
    CBAVD 1745heterozygoteVUS3 - Cis
    CFTR-RD-causing- Undef
    Asymptomatic compound heterozygote 2966heterozygoteCF-causing - Trans
    Asymptomatic compound heterozygote 3257heterozygoteVUS3 - Cis
    CF-causing - Trans
    Asymptomatic compound heterozygote 5601heterozygoteCF-causing - Trans
    Asymptomatic compound heterozygote 2808heterozygotevarying clinical consequence- Undef
    Asymptomatic compound heterozygote 5602heterozygoteVUS3 - Cis
    VUS3 - Trans
    Asymptomatic compound heterozygote 4358heterozygoteCF-causing - Trans
    Asymptomatic compound heterozygote 4422heterozygoteVUS3 - Cis
    VUS3 - Trans
    Asymptomatic compound heterozygote 4345heterozygoteCF-causing - Trans
    Asymptomatic compound heterozygote 5964heterozygoteVUS3 - Cis
    CF-causing - Trans
    Asymptomatic compound heterozygote 4260heterozygoteVUS3 - Cis
    CFTR-RD-causing - Trans
    Asymptomatic compound heterozygote 4961heterozygoteCF-causing- Undef
    Asymptomatic compound heterozygote 5141heterozygoteVUS3 - Trans
    Asymptomatic compound heterozygote 5073heterozygote
    Asymptomatic compound heterozygote 5081heterozygote
    Asymptomatic compound heterozygote 5705heterozygoteVUS3- Undef
    Asymptomatic compound heterozygote 2142heterozygoteCF-causing- Undef
    Asymptomatic compound heterozygote 1290heterozygoteCFTR-RD-causing - Trans
    Pending non-CF 4825heterozygoteVUS3 - Cis
    varying clinical consequence - Trans
    Bronchiectasis 2243heterozygoteCF-causing- Undef
    Bronchiectasis 2838heterozygoteCFTR-RD-causing- Undef
    Bronchiectasis 6192heterozygoteCF-causing- Undef
    Bronchiectasis 4308heterozygote
    Bronchiectasis 5126heterozygoteVUS3- Undef
    Bronchiectasis 1844heterozygoteCF-causing- Undef
    Bronchiectasis 5669heterozygoteVUS3 - Cis
    VUS3 - Trans
    Bronchiectasis 6282heterozygoteVUS3 - Cis
    CF-causing - Trans
    Bronchiectasis 4974heterozygoteVUS3- Undef
    Pancreatitis 2984heterozygoteCFTR-RD-causing- Undef
    Pancreatitis 3072heterozygoteCF-causing - Trans
    Pancreatitis 5340heterozygoteVUS3- Undef
    Pancreatitis 2318heterozygote
    Pancreatitis 2338heterozygoteVUS3 - Cis
    Pancreatitis 2748heterozygoteCFTR-RD-causing- Undef
    Pancreatitis 6201heterozygote
    Pancreatitis 4240heterozygoteCF-causing - Trans
    VUS3 - Trans
    Pancreatitis 4258heterozygote
    Pancreatitis 4301heterozygote
    Pancreatitis 5458heterozygoteVUS3- Undef
    Pancreatitis 5740heterozygoteVUS3 - Cis
    Pancreatitis 2065heterozygote
    Pancreatitis 4996homozygotec.1210-34_1210-6TG[11]T[5] - Trans
    c.1327G>T - p.(Asp443Tyr) - Trans
    Aquagenic palmoplantar keratoderma 6276heterozygoteCF-causing - Trans
    Aquagenic palmoplantar keratoderma 4660heterozygotevarying clinical consequence - Trans
    Aquagenic palmoplantar keratoderma 5086heterozygotelikely CFTR-RD- Undef
    Pending 2360heterozygote
    Pending 2843heterozygoteVUS3 - Cis
    CF-causing - Trans
    Pending 3236heterozygoteCF-causing - Trans
    Pending 4304heterozygoteVUS3 - Cis
    Pending 4505heterozygoteCF-causing - Trans
    CRS-NP 3043heterozygoteVUS3 - Cis
    CF-causing - Trans
    CRS-NP 4805heterozygote
    Pending (NBS) 4420heterozygoteCFTR-RD-causing - Trans
    Pending (NBS) 4806heterozygote
    Pending (NBS) 6010heterozygoteCF-causing- Undef


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



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