Description
The CFTR c.3808G>A variant is predicted to result in the amino acid substitution p.Asp1270Asn. This variant has been reported in patients with congenital bilateral absence of the vas deferens (Anguiano et al. 1992. PubMed ID: 1545465; Oates et al. 1993. PubMed ID: 8343799; Padoa et al. 1999. PubMed ID: 9950364; Chamayou et al. 2020. PubMed ID: 32357917), but has also been observed in the homozygous or compound heterozygous state in asymptomatic individuals (Terlizzi et al. 2017. PubMed ID: 27738188; Chamayou et al. 2020. PubMed ID: 32357917). The p.Asp1270Asn variant resulted in minimal disruption to CFTR processing in HeLa and FRT cells, suggesting normal CFTR maturation (Fanen et al. 1999. PubMed ID: 10386624; Sosnay et al 2013. PubMed ID: 23974870; Van Goor et al. 2014. PubMed ID: 23891399). In FRT cells, the p.Asp1270Asn variant retained nearly half of wild-type CFTR chloride channel transport function, which was restored to wild-type levels with ivacaftor, suggesting a mild defect in channel conductance (Sosnay et al 2013. PubMed ID: 23974870; Van Goor et al. 2014. PubMed ID: 23891399). Consistent with this, in HeLa cells, the p.Asp1270Asn variant impaired cAMP-responsive anion conductance of CFTR (Fanen et al. 1999. PubMed ID: 10386624). The p.Asp1270Asn variant is documented in 57 patients in the CFTR2 database with an average sweat chloride concentration of 57 mEq/L, compared to an average of 96 mEq/L for all patients in CFTR2 with two CF-causing variants (cftr2.org). This variant is reported in up to ~1.4% of alleles in individuals of African descent in gnomAD, including three homozygous individuals of unknown phenotype. In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/7164). In summary, due to conflicting genetic and functional evidence, the clinical significance of the p.Asp1270Asn variant is uncertain. Of note, the p.Arg74Trp and p.Asp1270Asn variants have been reported in linkage (on the same allele) and are collectively referred to as p.[Arg74Trp;Asp1270Asn]. Variant phasing information in gnomAD indicates that the p.Arg74Trp and p.Asp1270Asn variants likely occur in cis within the African, Latino/Admixed American and European (non-Finnish) subpopulations, but may rarely occur independently of each other. Consistent with this, one study observed that 94% of individuals carrying the p.Asp1270Asn variant also carried the p.Arg74Trp variant (Sugarman et al. 2004. PubMed ID: 15371903). The p.[Arg74Trp; Asp1270Asn] complex allele has been reported in compound heterozygous individuals with CBAVD and obstructive bronchitis (Claustres et al. 2004. PubMed ID: 15287992; Terlizzi et al. 2017. PubMed ID: 27738188; Chamayou et al. 2020. PubMed ID: 32357917), but has also been observed in the compound heterozygous state in asymptomatic individuals (Verlingue et al. 1993. PubMed ID: 7513889; Claustres et al. 2004. PubMed ID: 15287992; Terlizzi et al. 2017. PubMed ID: 27738188). In HeLa cells, the p.[Arg74Trp; Asp1270Asn] variant did not affect CFTR processing but did result in impaired cAMP-responsive anion conductance (Fanen et al. 1999. PubMed ID: 10386624). The authors suggest that both variants together may lead to a synergistic effect to further impair CFTR function than either variant in isolation (Fanen et al. 1999. PubMed ID: 10386624; Claustres et al. 2004. PubMed ID: 15287992). In addition, Sosnay et al. in a comprehensive study of CFTR variants classified these variants as “indeterminate” (Sosnay et al 2013. PubMed ID: 23974870). In ClinVar, the complex allele p.[Arg74Trp; Asp1270Asn] is interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/977735). In summary, due to the conflicting genetic and functional evidence, the clinical significance of the complex p.[R74W; D1270N] variant is also uncertain.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
