ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1399C>T (p.Leu467Phe)

gnomAD frequency: 0.00005  dbSNP: rs1800089
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001824591 SCV000696841 uncertain significance not specified 2023-04-26 criteria provided, single submitter clinical testing Variant summary: CFTR c.1399C>T (p.Leu467Phe) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251294 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (4e-05 vs 0.013), allowing no conclusion about variant significance. c.1399C>T has been reported in the literature in individuals affected with Cystic Fibrosis as well as CFTR-related disorders, however, often a second allele is not specified. In addition, the variant has been reported in multiple patients in cis with common pathogenic mutation F508del, in both internal samples and reported in the literature (Vecchio-Pagan_2016, Costa_2011, Sermet-Gaudelus_2010, Terlizzi_2020), suggesting the variant may be benign. The variant has also been reported in an internal sample with two pathogenic mutations, providing additional supporting evidence for a benign role. However, recent cases and functional evidence has suggested that p.Leu467Phe, as part of a complex allele with F508del, may impact a patients response to CFTR modulators (Kondratyeva_2022, Sondo_2022). In a cell-based functional study, CFTR-p.Leu467Phe tested alone had a significantly reduced maturation compared to CFTR-WT and a reduced channel activity (Baatallah_2018). However, it remains unclear the impact of this variant in relation to human disease. The following publications have been ascertained in the context of this evaluation (PMID: 22020151, 29271547, 32026723, 32292813, 10923036, 28603918, 21783433, 16436643, 18716917, 24106596, 19202204, 20538955, 26437683, 22892530, 32150665, 26436105, 27917292, 36286063, 35328596). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: Five labs classify as VUS, two as likely pathogenic, and three as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics RCV000577709 SCV000886158 likely pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000577709 SCV001167224 likely benign Cystic fibrosis 2019-08-22 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000588804 SCV001250506 uncertain significance not provided 2022-03-01 criteria provided, single submitter clinical testing CFTR: PS4:Moderate, PP4
Baylor Genetics RCV000577709 SCV001523280 uncertain significance Cystic fibrosis 2020-06-04 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic RCV000588804 SCV001714236 uncertain significance not provided 2020-06-10 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000577709 SCV001822052 likely benign Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588804 SCV002047253 uncertain significance not provided 2021-03-16 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000577709 SCV002573880 likely pathogenic Cystic fibrosis 2022-09-05 criteria provided, single submitter curation This variant was identified in 4 unrelated patients 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_SUP, PM2_SUP, PM3, PP3, PP4
Ambry Genetics RCV000577709 SCV002702281 likely benign Cystic fibrosis 2017-12-22 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000577709 SCV003467372 uncertain significance Cystic fibrosis 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 467 of the CFTR protein (p.Leu467Phe). This variant is present in population databases (rs1800089, gnomAD 0.009%). This variant has been observed in several individuals affected with CFTR-related conditions (PMID: 16436643, 29271547, 21783433, 10923036, 26436105, 27917292, 24106596, 19202204, 29504914). However, in most of these individuals this variant was observed in cis with a pathogenic allele, which suggests that this c.1399C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 53246). 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: 29271547). This variant disrupts the p.Leu467 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20510657, 23891399, 23974870, 26708955). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577709 SCV000679106 not provided Cystic fibrosis no assertion provided literature only

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