ClinVar

Description

The CFTR c.1367T>C; p.Val456Ala variant (rs193922500) is reported as a CF-causing variant in the CFTR2 database, and CF patients with this variant are likely to be pancreatic sufficient (see CFTR2 database link). This variant is reported in the literature in both the homozygous and compound heterozygous states in CF patients (McCormick 2002, Uppaluri 2012); however, one report of an asymptomatic patient who is homozygous for this variant, suggests that it may be a mild CF variant (Strom 2003). Functional analysis of the variant protein shows approximately 4% of wildtype protein activity (Raraigh 2018). This variant is reported as likely pathogenic in ClinVar (Variation ID: 35821). It is found in the South Asian general population with an allele frequency of 0.16% (48/30028 alleles) in the Genome Aggregation Database. The valine at codon 456 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. Based on available information, this variant is considered to be likely pathogenic. REFERENCES CFTR2 database: https://cftr2.org/ McCormick J et al. Demographics of the UK cystic fibrosis population: implications for neonatal screening. Eur J Hum Genet. 2002 Oct;10(10):583-90. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Strom CM et al. Extensive sequencing of the cystic fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a comprehensive test. Genet Med. 2003 Jan-Feb;5(1):9-14. Uppaluri L et al. Clinical evidence that V456A is a Cystic Fibrosis causing mutation in South Asians. J Cyst Fibros. 2012 Jul;11(4):312-5.