ClinVar Genomic variation as it relates to human health

The p.R1438W variant (also known as c.4312C>T), located in coding exon 27 of the CFTR gene, results from a C to T substitution at nucleotide position 4312. The arginine at codon 1438 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in cis with p.F508del in an infant with an abnormal newborn screen; a third CFTR variant was detected on the opposite chromosome (Schrijver I et al. J Mol Diagn, 2005 May;7:289-99). In a second individual, this variant was confirmed in cis with p.F508del and in trans with p.Y1032C; the patient initially presented with an abnormal newborn screen with borderline sweat chloride levels and later presented with acute pancreatitis (Leonardi S et al. J Med Case Rep, 2013 Jul;7:188). In a cohort on individuals with CFTR-related disorders, this variant was detected in one individual with recurrent pancreatitis; however, complete genotype information was not provided (Amato F et al. J Mol Diagn, 2012 Jan;14:81-9). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.

Variant summary: CFTR c.4312C>T (p.Arg1438Trp) results in a non-conservative amino acid change located in the ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250892 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4312C>T has been reported in the literature in individuals who also carried another (potentially) pathogenic CFTR variant in trans, who had positive newborn screening, pancreatitis or cystic fibrosis (Schrijver_2005, Leonardi_2013, Vecchio-Pagan_2016), however in all of these individuals the variant was reported in cis (i.e. as a complex allele) with the common disease variant p.F508del. The variant was also reported in a case with recurrent pancreatitis, however, the genotype information was not provided (Amato_2012). These data therefore do not allow any conclusion about variant significance. The most pronounced variant effect resulted in approximately (Gt channel conductance) 61% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 22020151, 29271547, 26087173, 31883651, 23883480, 29569753, 15858154, 27917292, 38388235). ClinVar contains an entry for this variant (Variation ID: 53940). Based on the evidence outlined above, the variant was classified as uncertain significance.

The CFTR c.4312C>T variant is predicted to result in the amino acid substitution p.Arg1438Trp. This variant has been reported in individuals with cystic fibrosis, pancreatitis, or positive newborn screening; however, it has been reported in cis with a second CFTR variant, such as c.1521_1523del (p.Phe508del) in multiple individuals (Schrijver et al. 2005. PubMed ID: 15858154; Leonardi et al. 2013. PubMed ID: 23883480; referred to as R1438Y, Vecchio-Pagán et al. 2016. PubMed ID: 27917292; http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1406). An in vitro experimental study classified this variant as responsive to treatment with the CFTR modulator combination elexacaftor/tezacaftor/ivacaftor; however, the effect of this variant in combination with others it was previously reported with was unclear (Bihler et al. 2024. PubMed ID: 38388235). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.