ClinVar

Description

Variant summary: CFTR c.3409A>G (p.Met1137Val) results in a conservative amino acid change located in the transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 252866 control chromosomes (gnomAD v2.1, and publication data). c.3409A>G has been reported in the literature in compound heterozygous individuals affected with cystic fibrosis (CF) who carried a pathogenic variant in trans (e.g. Clarke_2018, Iuliano_2009), but was also reported in an individual with neonatal hypertrypsinaemia, but normal sweat test, who was compound heterozygous for the variant and the delta508 allele (Castellani_2001). The variant was also found in a patient diagnosed with congenital bilateral absence of the vas deferens (CBAVD), who was a compound heterozygote with a complex allele classified as pathogenic for CFTR-related disorders by our lab (El-Seedy_2012). In addition, the variant was reported in individuals affected with CF-related- or unspecified phenotypes (e.g. Durno_2002, El-Seedy_2012, Green_2010, Bombieri_1998, Trujillano_2015, Castellani_2001, Eski_2019 [No PMID]), however without strong evidence for causality (i.e. lack of second CFTR variant and co-segregation evidence). These data indicate that the variant may be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated decreased channel activity, but no visible effect on protein maturation (Vankeerberghen_1998). The following publications have been ascertained in the context of this evaluation (PMID: 7543317, 9921909, 8644755, 9804160, 22678879, 11303517, 20932301, 25910067, 12454843, 19587087, 26436105, 11845002, 30488522). ClinVar contains an entry for this variant (Variation ID: 53733). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.