ClinVar Genomic variation as it relates to human health

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1137 of the CFTR protein (p.Met1137Val). This variant is present in population databases (rs397508553, gnomAD 0.005%). This missense change has been observed in individual(s) with cystic fibrosis, bronchiectasis, congenital bilateral absence of vas deferens and hypertrypsinaemia (PMID: 7543317, 9921909, 11303517, 12454843, 22678879, 25910067, 26436105). ClinVar contains an entry for this variant (Variation ID: 53733). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CFTR function (PMID: 26436105). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.M1137V variant (also known as c.3409A>G), located in coding exon 21 of the CFTR gene, results from an A to G substitution at nucleotide position 3409. The methionine at codon 1137 is replaced by valine, an amino acid with highly similar properties. This variant has been detected in individuals with cystic fibrosis or congenital bilateral absence of the vas deferens who carried an additional pathogenic/likely pathogenic variant (Iuliano L et al. Am J Clin Nutr, 2009 Sep;90:477-84; El-Seedy A et al. Hum Mutat, 2012 Nov;33:1557-65; Jabr S et al. Prostaglandins Leukot Essent Fatty Acids, 2013 Aug;89:121-6; Clarke LA et al. Hum Mutat, 2019 Mar;40:326-334). However, it has also been detected in trans with p.F508del in a neonate who had elevated immunoreactive trypsinogen concentration, but normal sweat chloride level (Castellani C et al. J Med Genet, 2001 Mar;38:202-5). Based on internal structural analysis, M1137V is more disruptive than several internally pathogenic variants within the same transmembrane domain (Fiedorczuk K et al. Cell, 2022 Jan;185:158-168.e11). In a functional study, M1137V did not affect protein maturation, but significantly reduced cAMP-activated whole cell chloride currents (Vankeerberghen A et al. FEBS Lett., 1998 Oct;437:1-4). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis; however, it likely contributes to the development of a CFTR-related disorder. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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. Three of four 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. 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, BIhler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 9921909, 11303517, 30488522, 12454843, 22678879, 20932301, 19587087, 25910067, 8644755, 7543317, 11845002, 26436105, 9804160). ClinVar contains an entry for this variant (Variation ID: 53733). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.