ClinVar Genomic variation as it relates to human health

Variant summary: CFTR c.1687T>A (p.Tyr563Asn) results in a non-conservative amino acid change located in the ABC transporter-like, 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 8e-06 in 250432 control chromosomes. c.1687T>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis (example, McCague_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal CFTR activity in vitro (example, Han_2018). Multiple clinical diagnostic laboratories and an expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 563 of the CFTR protein (p.Tyr563Asn). This variant is present in population databases (rs121909006, gnomAD 0.0009%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 1376017, 2236053, 10923036, 12815607, 15858154, 17825628; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7114). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 10764788). For these reasons, this variant has been classified as Pathogenic.

the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both

PP3, PP5, PM2_strong, PS1, PS3

The p.Y563N pathogenic mutation (also known as c.1687T>A), located in coding exon 13 of the CFTR gene, results from a T to A substitution at nucleotide position 1687. The tyrosine at codon 563 is replaced by asparagine, an amino acid with dissimilar properties. This mutation was observed in a pancreatic sufficient individual with cystic fibrosis (CF) who was also heterozygous for a nonsense alteration; however, phase (cis or trans) was not determined (Kerem BS et al. Proc. Natl. Acad. Sci. U.S.A., 1990 Nov;87:8447-51). In another study, this mutation was observed in trans with a nonsense alteration in an individual with CF (Fichou Y et al. J. Cyst. Fibros., 2008 Mar;7:168-73). In vitro expression analysis revealed that the p.Y563N mutation results in decreased levels of mature CFTR protein (Van Oene M et al. J. Biol. Chem., 2000 Jun;275:19577-84). Based on the available evidence, the p.Y563N is classified as a pathogenic mutation.

Published functional studies demonstrate a damaging effect on protein expression and function (PMID: 29805046, 10764788, 30046002); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28603918, 30046002, 18361776, 10764788, 25489051, 17825628, 8956039, 1376017, 12815607, 10923036, 15858154, 1376016, 2236053, 34782259, 30888834, 28068001, 29805046)

The CFTR c.1687T>A variant is predicted to result in the amino acid substitution p.Tyr563Asn. This variant has been widely reported to be pathogenic for cystic fibrosis due to significantly decreased levels of mature CFTR protein (see for example, Kerem et al. 1990. PubMed ID: 2236053; Masica et al. 2015. PubMed ID: 25489051; Raraigh et al. 2018. PubMed ID: 29805046). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. All submitters classified the variant as pathogenic in the ClinVar database (https://preview.ncbi.nlm.nih.gov/clinvar/variation/7114/). This variant is interpreted as pathogenic.