ClinVar Genomic variation as it relates to human health

The CFTR c.2175dup; p.Glu726ArgfsTer4 variant (rs746418935) is reported in the literature in individuals affected with cystic fibrosis (Smit 1993, Sosnay 2013, Sugarman 2004). This variant is reported in ClinVar (Variation ID: 7185) and is found in the African population with an allele frequency of 0.03% (8/24,954 alleles) in the Genome Aggregation Database. 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. Furthermore, in vitro functional assays show a significant reduction in transcript expression (Smit 1993). Based on available information, this variant is considered to be pathogenic. References: Smit LS et al. An African-American cystic fibrosis patient homozygous for a novel frameshift mutation associated with reduced CFTR mRNA levels. Hum Mutat. 1993;2(2):148-51. PMID: 7686423. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870. Sugarman EA et al. CFTR mutation distribution among U.S. Hispanic and African American individuals: evaluation in cystic fibrosis patient and carrier screening populations. Genet Med. 2004 Sep-Oct;6(5):392-9. PMID: 15371903.

The p.Glu726ArgfsX4 variant in CFTR is commonly reported in individuals of African American ancestry and has been identified in the homozygous or compound heterozygous state with other disease-causing variants in CFTR in at least 2 individuals with clinical features of cystic fibrosis (Smit 1993 PMID: 7686423, Sugarman 2004 PMID: 15371903, Souza 2020 PMID: 32674983). In addition, it has been found in 59 patients in the CFTR2 database, the majority of which are pancreatic insufficient. This variant has also been reported by other clinical laboratories in ClinVar ((Variation ID 7185) and has been identified in 0.02% (9/41432) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 726 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the CFTR gene is an established disease mechanism in autosomal recessive cystic fibrosis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3.

Variant summary: CFTR c.2175dupA (p.Glu726ArgfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg., p.Leu732X and p.Arg764X). The variant allele was found at a frequency of 1.9e-05 in 1055458 control chromosomes. This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (1.9e-05 vs 0.013), allowing no conclusion about variant significance. c.2175dupA has been reported in the literature as a homozygous and compound heterozygous allele in numerous individuals affected with Cystic Fibrosis. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, which showed <10% of normal CFTR mRNA in patient cells (Smit_1993). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

NM_000492.3(CFTR):c.2175dupA(E726Rfs*4, aka 2307insA) 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.2175dupA(E726Rfs*4, aka 2307insA) 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.

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

This sequence change creates a premature translational stop signal (p.Glu726Argfs*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 (rs746418935, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 7686423, 15371903, 18456578). It is commonly reported in individuals of African American ancestry (PMID: 7686423, 15371903, 18456578). This variant is also known as c.2307insA. ClinVar contains an entry for this variant (Variation ID: 7185). For these reasons, this variant has been classified as Pathogenic.

The c.2175dupA pathogenic mutation, located in coding exon 14 of the CFTR gene, results from a duplication of A at nucleotide position 2175, causing a translational frameshift with a predicted alternate stop codon (p.E726Rfs*4). This mutation was described in the homozygous state in an African American individual with pancreatic insufficient cystic fibrosis, elevated sweat chloride levels, and severe lung disease (Smit LS et al. Hum. Mutat., 1993;2:148-51). The overall frequency of this allele in CF chromosomes has been observed at approximately 0.2%, with the highest occurrence in 2.0% of all African American CF chromosomes (Macek M et al. Am. J. Hum. Genet., 1997 May;60:1122-7; Bobadilla JL et al. Hum. Mutat., 2002 Jun;19:575-606). This pathogenic mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Of note, this alteration is also known as 2307insA in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

The CFTR c.2175dupA variant is predicted to result in a frameshift and premature protein termination (p.Glu726Argfs*4). This variant, also referred to as c.2307insA in the literature, has been reported in patients with cystic fibrosis (Smit et al. 1993. PubMed ID: 7686423; Table 2 in Castellani et al. 2008. PubMed ID: 18456578; Souza et al. 2020. PubMed ID: 32674983). This variant has been interpreted as pathogenic by the CFTR2 expert review panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/7185). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD. Frameshift variants in CFTR are expected to be pathogenic. Based on this evidence, we interpret this variant as pathogenic.

Variant interpretted as Pathogenic and reported on 01-07-2016 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.