Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 05, 2021 | The p.R1070Q pathogenic mutation (also known as c.3209G>A), located in coding exon 20 of the CFTR gene, results from a G to A substitution at nucleotide position 3209. The arginine at codon 1070 is replaced by glutamine, an amino acid with highly similar properties. Functional studies have shown that this mutation does not affect protein processing (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7), but it was observed to decrease the open probability of the channel (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45). This mutation has been reported as a variant of varying clinical consequence (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed March 30, 2018); when in trans with a second disease causing mutation it may result in cystic fibrosis, CFTR-related disorders, or no phenotype (Bombieri C et al. Semin Respir Crit Care Med, 2015 Apr;36:180-93; Girardet A et al. Eur. J. Hum. Genet., 2016 Apr;24:469-78). Of note, this mutation has also been observed as part of a complex allele with p.S466* (Krasnov KV et al. Hum. Mutat., 2008 Nov;29:1364-72; Lucarelli M et al. Mol. Med., 2015 Apr;21:257-75). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1070 of the CFTR protein (p.Arg1070Gln). This variant is present in population databases (rs78769542, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with cystic fibrosis or congenital bilateral absence of the vas deferens. While this variant is commonly found in cis with p.Ser466*, it has also been observed without p.Ser466* in affected individuals and is expected to be causative for CFTR-related conditions whether p.Ser466* is present or not (PMID: 12955726, 18467194, 18951463, Invitae). Some individuals with this variant may present with milder symptoms. ClinVar contains an entry for this variant (Variation ID: 35866). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 8662892, 8702904, 11242048, 23891399). This variant disrupts the p.Arg1070 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7539342, 16189704, 21520337, 23974870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed missense c.3209G>A(p.Arg1070Gln) variant in CFTR gene has been observed in the compound heterozygous state in multiple individuals affected with cystic fibrosis (Feldmann et al., 2003, Krasnov et al., 2008). Experimental studies have shown that this missense change affects CFTR function (Van Goor et al., 2014). The p.Arg1070Gln variant has been reported with allele frequency of 0.06% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg1070Gln in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. In absence of another reportable variant in CFTR gene, the molecular diagnosis is not confirmed. - |
Uncertain significance, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 1 patient 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: PS3, PM3, PM5, PP3, PP4, BS2 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | May 18, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 23, 2024 | Variant summary: CFTR c.3209G>A (p.Arg1070Gln) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251348 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (0.00061 vs 0.013), allowing no conclusion about variant significance. This variant has been reported in several patients with classic CF, non-classic CF, or CBAVD and in several patients it was observed in cis with p.S466X forming a complex allele (example, Krasnov_2008, Mercier_1994, Kanavakis_1005, Savov_1994, Tzetis_2007, Feldmann_2003, Sosnay_2013, Furlan_2016, Lucarelli_2015, Palermo_2016, Behar_2017, Ivanov_2018, Salvatore_2019, Frentescu_2008, Noni_2023). Available patient data suggests that in compound heterozygotes, this variant typically results in mild disease such as CF/NC and/or CBAVD, while in cis with p.S466X variant, it causes classic CF (Krasnov_2008). However, the variant has also been reported in trans with F508del in a CF patient with sweat chloride levels >60 mmol/L (without p.S466X in cis; Noni_2023). Although this variant is able to mature and reach the cell surface and was found to have no significant effect on chloride transport, it was found to cause relatively subtle channel defects with functional consequences of a lower open probability of the channel, lower cyclic AMP-stimulated iodide efflux, and lower bicarbonate transport (Seibert_1996, Krasnov_2008, Sosnay_2013, Choi_2001). In these studies, maturation assays were performed on HEK-293, MDCK and COS cells, and channel function and channel transport assays were performed on HEK293 and CHO cells. In FRT cells, however, chloride transport as well as maturation was found to be significantly reduced for this variant (20.5% of normal but increased to 32.9% of normal after Ivacaftor treatment) (Van Goor_2014). These functional differences might be due to the use of different cell lines in different studies and technical backgrounds; however, all of these studies are suggestive of a mild functional impairment for the variant in isolation. A different variant affecting the same codon has been classified as pathogenic by our lab (c.3208C>T, p.Arg1070Trp), supporting the critical relevance of codon 1070 to CFTR protein function. However, due to the varying and typically mild disease phenotypes in individuals with this variant, as well as the allele frequency and presence of homozygotes in the gnomAD database, this variant likely represents a hypomorphic allele. The following publications have been ascertained in the context of this evaluation (PMID: 16049310, 12955726, 12007216, 17489851, 11242048, 15880796, 18951463, 7512860, 1284534, 7544320, 7529319, 19707853, 8662892, 23974870, 23891399, 25087612, 26014425, 25910067, 27209008, 27171515, 18467194, 28546993, 29504914, 30930780, 30561903, 36272381). ClinVar contains an entry for this variant (Variation ID: 35866). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Aug 29, 2019 | - - |