ClinVar Genomic variation as it relates to human health

BP2, PM2, PM3_supporting

The p.I1203V variant (also known as c.3607A>G), located in coding exon 22 of the CFTR gene, results from an A to G substitution at nucleotide position 3607. The isoleucine at codon 1203 is replaced by valine, an amino acid with highly similar properties. This variant was reported in a homozygous state in an infant with obstructive lung disease, airway colonization by Pseudomonas aeruginosa, and a positive sweat test (Fredj SH et al. Genet Test Mol Biomarkers, 2009 Oct;13:577-81). This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

The CFTR c.3607A>G; p.Ile1203Val variant (rs75647395) is reported in the literature in several individuals with symptoms or a diagnosis of cystic fibrosis (Behar 2017, Cutting 1992, Fredj 2009). This variant has been reported to occur on the same chromosome as a pathogenic CFTR variant, p.Ser1255Ter (Cutting 1992). Indeed, a number of affected individuals in the literature or identified in testing at ARUP Laboratories carried both the p.Ile1203Val variant and p.Ser1255Ter (Behar 2017, Cutting 1992), although one affected individual with a homozygous p.Ile1203Val variant was reported without p.Ser1255Ter (Fredj 2009). The p.Ile1203Val variant is found on only two chromosomes (2/250372 alleles) in the Genome Aggregation Database. The valine at codon 1203 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Although available information does not strongly suggest that the p.Ile1203Val variant is disease-causing on its own, due to limited information, its clinical significance is uncertain at this time. References: Behar DM et al. Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening. Mol Genet Genomic Med. 2017 Feb 19;5(3):223-236. Cutting GR et al. Analysis of four diverse population groups indicates that a subset of cystic fibrosis mutations occur in common among Caucasians. Am J Hum Genet. 1992 Jun;50(6):1185-94. Fredj SH et al. Cystic fibrosis transmembrane conductance regulator mutation spectrum in patients with cystic fibrosis in Tunisia. Genet Test Mol Biomarkers. 2009 Oct;13(5):577-81.

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1203 of the CFTR protein (p.Ile1203Val). This variant is present in population databases (rs75647395, gnomAD 0.007%). This missense change has been observed in individual(s) with cystic fibrosis (CF) and CF carried this combination of variants (PMID: 1376017, 19715466, 28546993; p.Ser1255*). ClinVar contains an entry for this variant (Variation ID: 53778). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function. 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.3607A>G (p.Ile1203Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250372 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3607A>G has been reported in the literature in several individuals diagnosed with Cystic Fibrosis (e.g., Cutting_1992, Behar_2017, Fredj_2009, Hamouda_2020, daSilvaFilho_2021). At least two of the individuals carried a known pathogenic CFTR variant, c.3764C>A (p.Ser1255X) in cis (Cutting_1992, Behar_2017), providing supporting evidence for a benign role. However, the variant was also reported in the homozygous state in at least one individual with obstructive lung disease, airway colonization by Pseudomonas aeruginisa and a positive sweat test (67mM; e.g., Fredj_2009, Hamouda_2020). Mutational scanning by DGGE was utilized in this report, therefore the possibility of a missed mutation cannot be entirely ruled out. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. This variant was identified in an internal specimen with the combination of c.1853T>C (classified as VUS-possibly pathogenic)/c.3607A>G/c.3764C>A (classified as Pathogenic). Although the phase was not determined at time of testing, the genotype appears similar to that reported in the literature. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28546993, 1376017, 19715466, 33402933, 32819855). Six ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant in isolation was classified as VUS-possibly benign.

The CFTR c.3607A>G variant is predicted to result in the amino acid substitution p.Ile1203Val. This variant was reported in the homozygous state in an individual with cystic fibrosis (Fredj et al. 2009. PubMed ID: 19715466) and was identified in a cohort of individuals with cystic fibrosis (da Silva Filho et al. 2021. PubMed ID: 32819855). However, this variant was also reported to occur in cis with the p.Ser1255* variant in an African-American patient with symptoms diagnostic of cystic fibrosis (Cutting et al. 1992. PubMed ID: 1376017). This variant was also described in an affected individual who carried both p.Phe508del and p.Ser1255* (phase not determined, Behar et al. 2017. PubMed ID: 28546993). In ClinVar, multiple laboratories classify the c.3607A>G (p.Ile1203Val) variant as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/53778/). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.