ClinVar Genomic variation as it relates to human health

The p.R31L variant (also known as c.92G>T), located in coding exon 2 of the CFTR gene, results from a G to T substitution at nucleotide position 92. The arginine at codon 31 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in an individual with elevated sweat chloride levels and virtually normal pulmonary and pancreatic function; however, no second CFTR alteration was identified (Zielenski J, Hum. Mutat. 1995; 5(1):43-7). In vitro protein studies show that this alteration causes a reduction in the surface expression of the CFTR protein (Jurkuvenaite A, J. Biol. Chem. 2006 Feb; 281(6):3329-34; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). A different alteration located at the same position, p.R31H, has been identified in an individual with chronic bronchitis without a second alteration (Nakano E et al. Dig. Dis. Sci., 2015 May;60:1297-307; El-Seedy A et al. Cell. Mol. Biol. (Noisy-le-grand), 2016 Nov;62:21-28). Another different alteration located at the same position, p.R31C, has been detected as homozygous in an unaffected individual and heterozygous in individuals with cystic fibrosis symptoms, oligospermia, and pancreatitis (Ghanem N et al. Genomics 1994; 21:434-6; Gallati S et al. Reprod. Biomed. Online 2009; 19:685-94; Gomez Lira M et al. Pancreatology 2001; 1:538-42). In addition, the p.R31C alteration was shown to cause a reduction in the surface expression of the CFTR protein and occurred in fewer patients with pancreatitis than in healthy control individuals (Jurkuvenaite A et al. J. Biol. Chem. 2006; 281:3329-34; LaRusch et al. PLoS Genet, 2014; 10(7):e1004376). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

This variant has been previously reported in patients with a phenotypic consistent with cystic fibrosis and is currently classified as a variant of uncertain significance by three submitters in ClinVar. Functional studies have shown that this variant may lead to reduced protein function, however the impact of this variant is not completely understood at this time. Additionally, this CFTR variant (rs149353983) is rare (<0.1%) in large population datasets (gnomAD: 11/282294 total alleles; 0.0039%; no homozygotes). Two bioinformatic tools queried predict that this substitution would be tolerated, and the arginine residue at this position is evolutionarily conserved across most species assessed. The clinical significance of c.92G>T is uncertain at this time.

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 31 of the CFTR protein (p.Arg31Leu). This variant is present in population databases (rs149353983, gnomAD 0.008%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 12454843). ClinVar contains an entry for this variant (Variation ID: 54087). 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: 16339147). 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.

Variant summary: CFTR c.92G>T (p.Arg31Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251968 control chromosomes. c.92G>T has been reported in the literature as a heterozygous non-informative genotype (second allele not specified) in a 24 year old initially reported with pulmonary symptoms at age 5.7 years but virtually normal pulmonary and pancreatic functions at age 24 despite an elevated sweat chloride level (90.8 mmol/L) (example, Zielenski_1995); in compound heterozygosity with p.F508del in at-least 7 individuals with a mean sweat chloride level of 37 mmol/L in the CFTR-2 database (example, McCague_2019, Munck_2020); a non-informative genotype in the South African CF registry (SACFR) (example, Zampoli_2021). These data do not allow any conclusion about variant significance. At least three publications report conflicting experimental evidence evaluating an impact on protein function in-vitro (example, Jurkuvenalte_2006, Raraigh_2018, Bihler_2024). The most pronounced variant effect results in diminished channel activity compared to wild-type (<10% of WT) in one study (Jurkuvenalte_2006), an indeterminate level of channel activity (56% of WT) in another (Raraigh_2018) and approximately (Gt channel conductance) 22% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 18193900, 17098864, 18306312, 17235394, 17098482, 7526685, 16251901, 31036917, 38388235, 16339147, 30888834, 15536480, 31916691, 29805046, 34996830, 34583889, 34350279, 7537150). ClinVar contains an entry for this variant (Variation ID: 54087). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.