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

gnomAD frequency: 0.00005  dbSNP: rs1800089

Total submissions: 15

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	2024-08-20	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 estimated 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 the common pathogenic mutation F508del, in both internal samples and reported in the literature (e.g. Vecchio-Pagan_2016, Costa_2011, Sermet-Gaudelus_2010, Terlizzi_2020, Kondratyeva_2022), 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 patient response to CFTR modulators, although it does not necessarily increase the severity of disease symptoms (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, the impact of this variant in relation to human disease remains unclear. The following publications have been ascertained in the context of this evaluation (PMID: 20538955, 36286063, 32292813, 32026723, 32150665, 29271547, 27917292, 26436105, 28603918, 26437683, 36142302, 21783433, 22892530, 24106596, 22020151, 16436643, 19202204, 10923036, 18716917, 35328596, 38388235, 35365085). ClinVar contains an entry for this variant (Variation ID: 53246). 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: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003884342	SCV004698103	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-02-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000577709	SCV004807023	likely pathogenic	Cystic fibrosis	2024-03-26	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577709	SCV000679106	not provided	Cystic fibrosis		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004734603	SCV005362777	uncertain significance	CFTR-related disorder	2024-09-23	no assertion criteria provided	clinical testing	The CFTR c.1399C>T variant is predicted to result in the amino acid substitution p.Leu467Phe. This variant has been reported along with p.Phe508del in a non-affected individual (Sobczyriska-Tomaszewska et al. 2013. PubMed ID: 22892530). It has been reported in the heterozygous state in individuals with cystic fibrosis or cystic fibrosis related disorders, without indication of a second pathogenic variant (Elahi et al. 2006. PubMed ID: 16436643; Amato et al. 2011. PubMed ID: 22020151). This variant has been reported as a complex allele (variants in cis on the same allele) with p.Phe508del in individuals with cystic fibrosis. Some of these individuals the complex allele was present alone and in other cases p.Phe508del was found in trans on the other allele (Raraigh et al. 2021. PubMed ID: 34782259; Petrova et al. 2022. PubMed ID: 35365085). There was no difference in disease severity when comparing patients with the complex allele to those who were homozygous for p.Phe508del (Petrova et al. 2022. PubMed ID: 35365085). Minigene analysis using HEK293 cells showed this variant affects protein maturation and channel activity, and also demonstrated that p.Phe508del alone recovers with corrector/potentiator treatment; however, this same treatment was ineffective for the complex allele (Baatallah et al. 2018. PubMed ID: 29271547). An alternate nucleotide change affecting the same amino acid (p.Leu467Pro) has been reported to be pathogenic (Sosnay et al. 2013. PubMed ID: 23974870; Internal Data, PreventionGenetics). This variant is reported in 0.0085% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant has conflicting classifications in ClinVar ranging from likely benign to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/53246/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.