ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.44T>C (p.Leu15Pro) (rs1562876459)

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Total submissions: 4
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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, Molecular Genetics and Genomics,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.
Invitae RCV000785636 SCV001206011 uncertain significance Cystic fibrosis 2019-02-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 15 of the CFTR protein (p.Leu15Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with cystic fibrosis and congenital bilateral absence of the vas deferens (PMID: 23687349, 20100616). This variant has been reported to affect CFTR protein function (PMID: 20351098). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000785636 SCV001363737 pathogenic Cystic fibrosis 2019-03-25 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 245566 control chromosomes (gnomAD). 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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