Submissions for variant NM_000492.4(CFTR):c.264A>C (p.Leu88Phe)

gnomAD frequency: 0.00003  dbSNP: rs149662778

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001234763	SCV001407422	uncertain significance	Cystic fibrosis	2022-10-03	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 88 of the CFTR protein (p.Leu88Phe). This variant is present in population databases (rs149662778, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 961121). 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. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001530071	SCV001474164	uncertain significance	not provided	2020-03-15	criteria provided, single submitter	clinical testing	The CFTR c.264A>C; p.Leu88Phe variant (rs149662778), to our knowledge, is not reported in the medical literature but is reported in the Leiden open variation database (see link). This variant is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 88 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Leu88Phe variant is uncertain at this time. References: Link to Leiden open variation database: https://databases.lovd.nl/shared/variants/0000256278#00000116
Genome-Nilou Lab	RCV001234763	SCV002027341	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001234763	SCV002739811	uncertain significance	Cystic fibrosis	2023-03-14	criteria provided, single submitter	clinical testing	The p.L88F variant (also known as c.264A>C), located in coding exon 3 of the CFTR gene, results from an A to C substitution at nucleotide position 264. The leucine at codon 88 is replaced by phenylalanine, an amino acid with highly similar properties. An alternate amino acid substitution at this codon, p.L88S, was reported in a cystic fibrosis cohort; however, clinical details were limited (Hughes DJ et al. Hum. Mutat., 1996;8:340-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530071	SCV001744651	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001530071	SCV001951021	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001530071	SCV001968426	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001834032	SCV002080102	uncertain significance	CFTR-related disorders	2018-08-21	no assertion criteria provided	clinical testing