ClinVar

Description

The CFTR c.3200C>T; p.Ala1067Val variant (rs1800114) has been reported in an individual with congenital absence of vas deferens (CBAVD), who carries the severe pathogenic F508del on the other chromosome (Jezequel 1995). Additionally, a different variant at this codon, p.Ala1067Pro, has been reported in an individual with CBAVD who also carries F508del (see database link), and a p.Ala1067Thr change has been reported in a cystic fibrosis (CF) patient with pancreatic insufficiency who also carries F508del (Ferec 1992). The p.Ala1067Thr variant was shown by functional analysis to have reduced CFTR maturation and chloride transport activity compared to wild type protein (Van Goor 2014). A fourth variant at this codon, p.Ala1067Asp, was found homozygously in a CF patient with mild pulmonary disease, and pancreatic insufficiency (see database link). The p.Ala1067Val variant is reported in ClinVar (Variation ID: 53683), and observed in general population databases at frequencies of 0.008 percent (1/13006 alleles, Exome Variant Server), and 0.001 percent (3/245722 alleles, Genome Aggregation Database). The alanine at codon 1067 is highly conserved, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Based on the above information, this variant is suspected to be mildly pathogenic. REFERENCES: Link to ClinVar database for p.Ala1067Val: https://www.ncbi.nlm.nih.gov/clinvar/variation/53683/ Link to SickKids database for p.Ala1067Pro: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1631 Link to SickKids database for p.Ala1067Asp: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1200 Ferec C et al. Detection of over 98% cystic fibrosis mutations in a Celtic population. Nat Genet. 1992 Jun;1(3):188-91. Jezequel P et al. Structural analysis of CFTR gene in congenital bilateral absence of vas deferens. Clin Chem. 1995 Jun;41(6 Pt 1):833-5. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36.