Submissions for variant NM_000492.4(CFTR):c.997C>T (p.Leu333Phe)

gnomAD frequency: 0.00002  dbSNP: rs193922533

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029550	SCV000052202	uncertain significance	not specified	2021-03-02	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.997C>T (p.Leu333Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 8e-06 in 251260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.997C>T has been reported in the literature in compound heterozygosity with the common pathogenic variant p.Phe508del in at least one individual affected with azoospermia or oligospermia (exact phenotypic details not provided, e.g. Rudnik-Schoneborn_2021). In addition the variant was reported in an individual with pancreatitis without strong evidence for causality (e.g. Giefer_2017). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. 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, until additional information becomes available, the variant was classified as uncertain significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002284355	SCV002573973	uncertain significance	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient 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: PM3, PM2_SUP, PP3
Ambry Genetics	RCV002284355	SCV002695441	uncertain significance	Cystic fibrosis	2024-07-09	criteria provided, single submitter	clinical testing	The p.L333F variant (also known as c.997C>T), located in coding exon 8 of the CFTR gene, results from a C to T substitution at nucleotide position 997. The leucine at codon 333 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been detected once in a cohort of individuals with acute recurrent and chronic pancreatitis (Giefer MJ et al. J. Pediatr., 2017 07;186:95-100). The p.Leu333Phe variant was identified in conjunction with p.Phe508del in one of 71 male patients with infertility, although phase was not confirmed (Rudnik-Schöneborn S et al. Hum Reprod, 2021 Feb;36:551-559). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002482913	SCV002782541	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-08-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002284355	SCV003504430	uncertain significance	Cystic fibrosis	2024-08-09	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 333 of the CFTR protein (p.Leu333Phe). This variant is present in population databases (rs193922533, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 28502372, 33374015). ClinVar contains an entry for this variant (Variation ID: 35895). 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%. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001723586	SCV005409331	uncertain significance	not provided	2023-11-15	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723586	SCV001958305	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723586	SCV001973436	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826517	SCV002078176	uncertain significance	CFTR-related disorder	2019-01-02	no assertion criteria provided	clinical testing