Description
Variant summary: Variant summary: CFTR c.1853T>C (p.Ile618Thr) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) and AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3). The variant allele was found at a frequency of 3.8e-05 in 262104 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (3.8e-05 vs 0.013), allowing no conclusion about variant significance. The variant, c.1853T>C, has been reported in the literature in compound heterozygosity with p.F508del or p.G542X in at-least three individuals affected with Non-classic (Pancreatically sufficient/mild phenotypes) Cystic Fibrosis (Macek 1997, Sousa 2012, Faria_2017). These data indicate that the variant may be associated with disease although multiple publications reporting the same patients confound distinct ascertainment (example, Vankeerberghen_1998, Marson_2012A, Marson_2013, Guimbellot_2017, Goncalves_2018, Pereira_2019, Faria_2017). Additionally, this variant has been observed in compound heterozygosity with other classic CFTR mutations such as p.A559T (c.1675G>A), p.F508del (c.1521_1523delCTT) and p.Ser1255X (c.3764C>A) in at-least three patients (a pair of sibs and two other distinct patients) sequenced for the CFTR gene at our laboratory. Detailed clinical information was available on one of these patients who was confirmed to have a known diagnosis of pancreatically insufficient CF with elevated sweat chloride levels, positivity for CF pathogens, severe baseline lung disease, and sinusitis. As the compound heterozygous genotypes observed in our laboratory are distinct (p.A559T and p.Ser1255X) from those reported in the literature, these data indicate that the variant is likely to be associated with disease (ACMG PP4). One publication, Pasyk_1998, reported this variant exhibits <50% of normal activity as chloride channel (ACMG PS3) while another publication, Vankeerberghen_1998, not providing primary data, reported this variant as resulting in abnormal processing leading to no or minimal functional CFTR proteins appearing at the cell membranes. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a complete consensus (Likely Pathogenic, n=5, Pathogenic, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
