Updates for c.1684G>A:
2024-10-14 Class updated from VUS1 to unclassified /probably non-CF




Variant NM_000492.4:c.1684G>A


Variant details:
Name NM_000492.4:c.1684G>A
Protein name NP_000483.3:p.(Val562Ile)
Genomic name (hg19)     chr7:g.117230411G>A    UCSC    
Genomic name (hg38) chr7:g.117590357G>A    UCSC
#Exon/intron exon 13
Legacy Name V562I
Class VUS
Subclass non-CF
complex allele in 21.74% of patients associated with
  • c.1210-34_1210-6TG[11]T[5] : 90.00%
  • c.1210-12T[5] : 10.00%
    • WT sequence TAATTTCCATTTTCTTTTTAGAGCA G TATACAAAGATGCTGATTTGTATTT
    Mutant sequence TAATTTCCATTTTCTTTTTAGAGCA A TATACAAAGATGCTGATTTGTATTT

    Other databases:
    dbSNP
    rs1800097



    Pathogenicity predictors:

    Functional studies:


    Reference PMID Splicing mRNA level Maturation Localization Channel fonction (Cl-) Bicarbonate
    Roxo-Rosa et al, 2006 17098864 ✓ ✓


    « ✓ » 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
    VNZ-TEZ-DIVA yesnono yes

    clinical and functional data presented above are provided by Vertex


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


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

    TOTAL NUMBER OF PATIENTS 46
    Asymptomatic compound heterozygote 2
    CF 5
    CFTR-RD36
    • Aquagenic palmoplantar keratoderma  1
    • Bronchiectasis  7
    • CBAVD  15
    • Other  4
    • Pancreatitis  9
    Pending 1
    Pending (NBS) 2




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

    Detailed genotypes:
    Phenotype Patient ID Variant status Additional variants
    CBAVD 2211heterozygoteCFTR-RD-causing- Undef
    CBAVD 4333heterozygotevarying clinical consequence- Undef
    CBAVD 6454heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing- Undef
    CBAVD 3318heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Trans
    CBAVD 919heterozygoteCFTR-RD-causing- Undef
    CF-causing- Undef
    CBAVD 725heterozygoteCFTR-RD-causing- Undef
    CF-causing- Undef
    CBAVD 475heterozygoteCFTR-RD-causing- Undef
    CF-causing- Undef
    CBAVD 400heterozygotevarying clinical consequence- Undef
    CF-causing- Undef
    CBAVD 1353heterozygoteCFTR-RD-causing - Cis
    CBAVD 1664heterozygotevarying clinical consequence- Undef
    CBAVD 1491heterozygoteCFTR-RD-causing - Cis
    CF-causing - Trans
    CBAVD 1464heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Trans
    CBAVD 1453heterozygoteCFTR-RD-causing - Cis
    varying clinical consequence - Trans
    CBAVD 389heterozygoteCFTR-RD-causing- Undef
    CBAVD 908homozygotec.1210-34_1210-6TG[11]T[5] - Trans
    c.1466C>T - p.(Ser489Leu) - Trans
    c.1684G>A - p.(Val562Ile) - Trans
    Bronchiectasis 5897heterozygoteCFTR-RD-causing - Cis
    Bronchiectasis 2217heterozygoteCFTR-RD-causing- Undef
    Bronchiectasis 2419heterozygoteCFTR-RD-causing- Undef
    Bronchiectasis 2580heterozygoteCFTR-RD-causing- Undef
    Bronchiectasis 777heterozygoteCFTR-RD-causing- Undef
    Bronchiectasis 1810heterozygoteCFTR-RD-causing- Undef
    Bronchiectasis 5001heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Trans
    VUS3 - Trans
    CF 5672heterozygoteCFTR-RD-causing - Cis
    CF-causing - Cis
    CF-causing - Trans
    CF 4942heterozygoteCFTR-RD-causing - Cis
    CF 5374heterozygoteCFTR-RD-causing - Cis
    CF-causing - Cis
    CF-causing - Trans
    CF 1285heterozygoteCFTR-RD-causing - Cis
    CF-causing - Cis
    CF-causing - Trans
    CF 780homozygotec.1210-34_1210-6TG[11]T[5] - Trans
    c.1684G>A - p.(Val562Ile) - Trans
    c.2215del - p.(Val739Tyrfs*16) - Trans
    Asymptomatic compound heterozygote 5606heterozygoteCFTR-RD-causing - Cis
    CF-causing - Trans
    Asymptomatic compound heterozygote 5220heterozygoteCFTR-RD-causing- Undef
    Aquagenic palmoplantar keratoderma 5822heterozygoteCFTR-RD-causing- Undef
    Other 4539heterozygoteCFTR-RD-causing- Undef
    Other 6226heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing - Trans
    VUS3- Undef
    Other 5763heterozygoteCFTR-RD-causing- Undef
    CF-causing- Undef
    Other 5823heterozygoteCFTR-RD-causing- Undef
    CF-causing- Undef
    VUS3- Undef
    Pending 5804heterozygoteCFTR-RD-causing - Cis
    varying clinical consequence - Trans
    VUS3 - Trans
    Pending (NBS) 4409heterozygoteCFTR-RD-causing - Cis
    CF-causing - Trans
    Pending (NBS) 6216heterozygoteCFTR-RD-causing - Cis
    CF-causing - Trans
    Pancreatitis 2162heterozygoteCFTR-RD-causing- Undef
    Pancreatitis 1940heterozygotevarying clinical consequence - Cis
    varying clinical consequence - Trans
    Pancreatitis 6388heterozygoteCFTR-RD-causing - Cis
    Pancreatitis 5891heterozygoteCFTR-RD-causing - Cis
    CFTR-RD-causing- Undef
    Pancreatitis 5870heterozygoteCFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    Pancreatitis 2486heterozygoteCFTR-RD-causing- Undef
    CFTR-RD-causing- Undef
    Pancreatitis 4913heterozygoteCFTR-RD-causing- Undef
    Pancreatitis 5456heterozygoteCFTR-RD-causing - Cis
    VUS3- Undef
    Pancreatitis 1673heterozygoteCFTR-RD-causing- Undef


    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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