Patient variants were diagnosed by a private laboratory elsewhere: Mendelics Análise Genômica S.A., São Paulo, Brazil (Organization ID: 500035). However, the lack of CF phenotypic features in this patient was so intriguing that it was decided to study family segregation. After segregation analysis using Direct Sanger Sequencing of exons 8, 11, and 15 of the CFTR gene in this family, the phase of CFTR variants in this patient was determined: - Proband is a compound heterozygote. Allele 1: [p.Arg851Leu; p.Thr351Ser]; inherited from the male progenitor Allele 2 : [p.Phe508del]; inherited from the female progenitor The patient has two siblings who have inherited only p.Phe508del from their female progenitor.
A very common way to verify the exocrine pancreatic sufficiency/insufficiency in Cystic Fibrosis patients is through the measurement of Fecal Elastase-1, a pancreatic enzyme that is not degraded in the digestion process and is intact in the feces. This is very strong evidence that this patient does not have CF. The kit used was ScheBo® Pancreatic Elastase 1TM Stoll Test kit (Biotech AG, Germany).
Description
This imprecision led to the belief that this variant is pathogenic. Despite this variant has been classified and reclassified over the course of time as pathogenic and lately as likely pathogenic (by Mendelics and Invitae), new functional evidence has shown that this variant does not alter CFTR function even when located in the same allele (in cis) as NM_000492.4(CFTR):2552G>T; p.Arg851Leu) and in trans with the most common pathogenic variant p.Phe508del (NM_000492.4(CFTR):1521_1523delCTT). Although in a pathogenic range due to its very low frequency in public databases (1000 Genomes, GnomAd Exons, GnomAd Genomes, etc., in people from different ethnicities), the aminoacid change promoted by this missense variant is practically synonymous for both amino acids residues are polar uncharged (at physiological pH), conserving the hydroxyl group in the side chain of this amino acid, basically having absent to little impact in the CFTR protein. Also, there is another missense variant in the same nucleotide position which has been classified as having uncertain significance (NM_000492.4(CFTR):c.1052C>T; p.Thr351Ile). Besides, prediction tools do not fully agree when predicting the deleteriousness of this variant. Therefore, the controversial data existing to date regarding this variant leads to the classification of uncertain significance. Brief Medical History: the patient was diagnosed with NBS and treated with pancreatic enzymes until the age of 2-3 y.o. The mother decided to stop giving any medication. Since then, the patient presented normal thrive and growth, normal stature, and was eutrophic throughout her life, which would not be expected given the patient's genotype. The patient is now 22 y.o. and has no history of chronic lung infections nor exacerbations or any other features compatible with Cystic Fibrosis. Sweat chloride tests have always been within borderline range (30-59 mM). Also, the patient is pancreatic-sufficient. In January 2020, the patient provided stool samples. Fecal elastase-1 levels in feces samples are within the normal range of the assay, which is a biomarker of pancreatic exocrine sufficiency. Other biochemical and hematological measurements to verify liver function were also normal throughout the patient's life.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | not applicable | not applicable | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
| 2 | inherited | no | not provided | not provided | not provided | | 1 | not provided | not provided | not provided |
