ClinVar Genomic variation as it relates to human health

The p.V855I variant (also known as c.2563G>A), located in coding exon 15 of the CFTR gene, results from a G to A substitution at nucleotide position 2563. The valine at codon 855 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported in a cohort of individuals with asthma (Lázaro C et al. Hum. Mutat., 1999;14:510-9), in an individual with a borderline sweat chloride level, nasal polyposis, and malnutrition (Seia M et al. Clin. Biochem., 2009 May;42:611-6), in a cohort of 381 patients with pancreatitis (Keiles S et al. Pancreas, 2006 Oct;33:221-7) and in a cohort of 250 cystic fibrosis patients from Istanbul diagnosed by two positive sweat chloride tests (Atag E et al. Pediatr Pulmonol, 2019 06;54:743-750). Of note, this alteration is commonly reported in conjunction with the p.R74W alteration in CFTR. 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.

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3, BP4

Variant summary: CFTR c.2563G>A (p.Val855Ile) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (InterPro) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 253420 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00016 vs 0.013), allowing no conclusion about variant significance. c.2563G>A has been reported in the literature in individuals affected with Asthma, Pancreatitis, and Cystic Fibrosis (Keiles_2006, Lazaro_1999, Seia_2009, Atag_2019, Bozdogan_2021, Cruz_2021). A recent study aiming to identify incompletely penetrant variants and interallelic interactions in autosomal recessive disorders reported no enrichment of this variant in the disease population (Miko_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30938940, 33572515, 33972190, 17003641, 10571949, 15536480, 25735457, 19318035, 34405919). ClinVar contains an entry for this variant (Variation ID: 53513). Based on the evidence outlined above, the variant was classified as uncertain significance.

The CFTR c.2563G>A variant is predicted to result in the amino acid substitution p.Val855Ile. This variant was reported in a number of individuals with CFTR-related disease (Seia et al 2009. PubMed ID: 19318035; Luo R et al 2020. PubMed ID: 32508047; Mikó Á et al 2021. PubMed ID: 34405919; Kars ME et al 2021. PubMed ID: 34426522). However, this variant is reported in 0.062% of alleles in individuals of South Asian descent in gnomAD, which is more common than expected for recessive disease. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.