Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| CFTR2 | RCV000785636 | SCV000924232 | pathogenic | Cystic fibrosis | 2018-08-31 | reviewed by expert panel | research | |
| ARUP Laboratories, |
RCV001000710 | SCV001157751 | likely pathogenic | not specified | 2018-07-29 | criteria provided, single submitter | clinical testing | The CFTR c.44T>C; p.Leu15Pro variant is reported in the literature in several individuals affected with cystic fibrosis (Lucarelli 2017, Trujillano 2013, SickKids CFTR database) and one individual with congenital bilateral absence of the vas deferens (Havasi 2010). In two instances, the p.Leu15Pro variant has been documented in cystic fibrosis-affected individuals carrying an additional pathogenic CFTR variant (Trujillano 2013, SickKids CFTR database). The p.Leu15Pro variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 15 is moderately conserved, but computational analyses (SIFT:damaging, PolyPhen-2:benign) predict conflicting effects of this variant on protein structure/function. The p.Leu15Pro variant and several nearby pathogenic missense variants occur in an N-terminal region required for binding Filamin A, an interaction that promotes CFTR stability and trafficking to the plasma membrane (Playford 2010, Thelin 2007). Computational modeling predicts that this variant disrupts the structure of the CFTR-Filamin A binding interface (Playford 2010), and a CFTR N-terminal p.Leu15Pro variant peptide fails to pull down detectable Filamin A (Playford 2010), suggesting the p.Leu15Pro variant protein may be unstable or improperly localized within the cell. Based on available information, this variant is considered to be likely pathogenic. References: SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/Home.html Havasi V et al. Fertil Steril. Association of cystic fibrosis genetic modifiers with congenital bilateral absence of the vas deferens. 2010 Nov;94(6):2122-7. Lucarelli M et al. A New Targeted CFTR Mutation Panel Based on Next-Generation Sequencing Technology. J Mol Diagn. 2017 Sep;19(5):788-800. Playford MP et al. Cystic fibrosis transmembrane conductance regulator interacts with multiple immunoglobulin domains of filamin A. J Biol Chem. 2010 May 28;285(22):17156-65. Thelin WR et al. Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR. J Clin Invest. 2007 Feb;117(2):364-74. Trujillano D et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet. 2013 Jul;50(7):455-62. |
| Labcorp Genetics |
RCV000785636 | SCV001206011 | pathogenic | Cystic fibrosis | 2023-11-08 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 15 of the CFTR protein (p.Leu15Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of CFTR-related disease (PMID: 20100616, 23687349, 28736296, 30763667; Invitae). ClinVar contains an entry for this variant (Variation ID: 634833). 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 expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 20351098). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000785636 | SCV001363737 | pathogenic | Cystic fibrosis | 2024-07-11 | criteria provided, single submitter | clinical testing | Variant summary: CFTR c.44T>C (p.Leu15Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250742 control chromosomes. c.44T>C has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Ruiz-Cabezas_2019, Lucarelli_2017, Trujillano_2013). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28736296, 30763667, 23687349). ClinVar contains an entry for this variant (Variation ID: 634833). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Ambry Genetics | RCV000785636 | SCV003996669 | pathogenic | Cystic fibrosis | 2023-05-27 | criteria provided, single submitter | clinical testing | The p.L15P pathogenic mutation (also known as c.44T>C), located in coding exon 1 of the CFTR gene, results from a T to C substitution at nucleotide position 44. The leucine at codon 15 is replaced by proline, an amino acid with similar properties. This alteration has been identified in multiple individuals with a clinical diagnosis of cystic fibrosis (CF) (Trujillano D et al. J Med Genet, 2013 Jul;50:455-62; Ruiz-Cabezas JC et al. Gene, 2019 May;696:28-32; Rueda-Nieto S et al. Orphanet J Rare Dis, 2022 Jun;17:222). This variant has <10% of wild type function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 05/26/2023). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Baylor Genetics | RCV003472322 | SCV004213531 | pathogenic | Bronchiectasis with or without elevated sweat chloride 1 | 2024-02-19 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV004792461 | SCV005413793 | pathogenic | not provided | 2024-05-22 | criteria provided, single submitter | clinical testing | PP3, PM2, PM3_strong, PS3 |