Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| CFTR2 | RCV000007662 | SCV000245885 | pathogenic | Cystic fibrosis | 2017-03-17 | reviewed by expert panel | research | |
| Counsyl | RCV000007662 | SCV000796919 | pathogenic | Cystic fibrosis | 2018-01-04 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000007662 | SCV000886188 | pathogenic | Cystic fibrosis | 2018-11-05 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759032 | SCV000888073 | pathogenic | not provided | 2022-06-08 | criteria provided, single submitter | clinical testing | The CFTR c.1682C>A (p.Ala561Glu) variant has been shown to result in severely reduced chloride conductance and CFTR processing, and a trafficking defect with protein mislocalization (PMID: 25489051 (2015), 23891399 (2014), 14623323 (2003)). The best available variant frequency is uninformative because it is below the disease allele frequency. It was found in at least one symptomatic patient. It is predicted to have a damaging effect on the protein. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, with phenotype known to be consistent with disease. |
| Baylor Genetics | RCV001004265 | SCV001163141 | pathogenic | Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation | criteria provided, single submitter | clinical testing | ||
| CFTR- |
RCV000007662 | SCV001169394 | pathogenic | Cystic fibrosis | 2018-01-29 | criteria provided, single submitter | curation | |
| Invitae | RCV000007662 | SCV001591070 | pathogenic | Cystic fibrosis | 2023-08-24 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects CFTR function (PMID: 14623323, 23891399). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 7240). This missense change has been observed in individuals with cystic fibrosis (PMID: 30996306). This variant is present in population databases (rs121909047, gnomAD 0.009%). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 561 of the CFTR protein (p.Ala561Glu). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000007662 | SCV001983488 | pathogenic | Cystic fibrosis | 2021-09-02 | criteria provided, single submitter | clinical testing | Variant summary: CFTR c.1682C>A (p.Ala561Glu) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 250250 control chromosomes. c.1682C>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis, including homozygotes (Mendes_2003, Hirtz_2004, Alonso_2007, Servidoni_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant results in defects in protein trafficking and channel function (Mendes_2003, Van Goor_2014). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=5) and likely pathogenic (n=1), including one expert panel (CFTR2) classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Ambry Genetics | RCV000007662 | SCV002715284 | pathogenic | Cystic fibrosis | 2023-08-19 | criteria provided, single submitter | clinical testing | The p.A561E pathogenic mutation (also known as c.1682C>A), located in coding exon 13 of the CFTR gene, results from a C to A substitution at nucleotide position 1682. The alanine at codon 561 is replaced by glutamic acid, an amino acid with dissimilar properties. The clinical presentation of individuals homozygous or compound heterozygous for p.A561E appears similar to individuals homozygous for p.F508del, although pulmonary disease is less severe (Mendes F et al. Biochem. Biophys. Res. Commun., 2003 Nov;311:665-71). This mutation is the second most common CFTR mutation in the Portuguese population, accounting for approximately 3% of cystic fibrosis alleles; it is a class II mutation which results in a misfolded CFTR protein that is subsequently degraded (Mendes F et al. Biochem. Biophys. Res. Commun., 2003 Nov;311:665-71; Roxo-Rosa M et al. Proc. Natl. Acad. Sci. U.S.A., 2006 Nov;103:17891-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, p.A561E is interpreted as a disease-causing mutation. |
| Baylor Genetics | RCV003473050 | SCV004213538 | pathogenic | Bronchiectasis with or without elevated sweat chloride 1 | 2023-03-28 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000007662 | SCV000027863 | pathogenic | Cystic fibrosis | 2003-11-21 | no assertion criteria provided | literature only | |
| Natera, |
RCV001826451 | SCV002080649 | pathogenic | CFTR-related disorders | 2017-09-01 | no assertion criteria provided | clinical testing |