ClinVar Genomic variation as it relates to human health

The CFTR c.2052dupA; p.Gln685ThrfsTer4 variant (rs121908786), also known as 2184insA, is reported in the literature in multiple individuals affected with the pancreatic insufficient form of cystic fibrosis (Amato 2012, Doerk 1994, Makukh 2010, Ooi 2012, Sosnay 2013, CFTR2 database). This variant is reported in ClinVar (Variation ID: 35838), and it is found on only seven chromosomes (7/249012 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Gln685ThrfsTer4 variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org Amato F et al. Extensive molecular analysis of patients bearing CFTR-related disorders. J Mol Diagn. 2012 Jan;14(1):81-9. PMID: 22020151. Doerk T et al. Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients. Hum Genet. 1994; 94(5):533-42. PMID: 7525450. Makukh H et al. A high frequency of the Cystic Fibrosis 2184insA mutation in Western Ukraine: genotype-phenotype correlations, relevance for newborn screening and genetic testing. J Cyst Fibros. 2010; 9(5):371-5. PMID: 20659818. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. PMID: 22658665. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870.

This variant was identified in 3 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1, PM3_VSTR, PM2_SUP, PP4

CFTR: PM3:Very Strong, PVS1, PM2

NM_000492.3(CFTR):c.2052dupA(Q685Tfs*4, aka 2184insA) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID: 23974870. Classification of NM_000492.3(CFTR):c.2052dupA(Q685Tfs*4, aka 2184insA) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

ACMG classification criteria: PVS1, PS4, PM2

PVS1,PM2,PM3_Very Strong,PP4

This sequence change creates a premature translational stop signal (p.Gln685Thrfs*4) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs746460279, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with cystic fibrosis, pancreatitis, and congenital absence of the vas deferens (PMID: 7525450, 9272157, 22020151, 23974870, 24586523). This variant is also known as 2184insA and c.2052_2053insA. ClinVar contains an entry for this variant (Variation ID: 35838). For these reasons, this variant has been classified as Pathogenic.

The observed frameshift variant c.2052dup (p.Gln685ThrfsTer4) in the CFTR gene has been reported previously in individuals with CFTR related disorders (Ziętkiewicz E, et al., 2014; Sosnay PR, et al., 2013). This variant is reported with the allele frequency 0.003% in the gnomAD Exomes. This variant causes a frameshift starting with codon Glutamine 685, changes this amino acid to Threonine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Gln685ThrfsTer4. It is submitted to ClinVar as Pathogenic by multiple submitters. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.