Submissions for variant NM_000492.4(CFTR):c.933C>G (p.Phe311Leu)

dbSNP: rs121909016

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007573	SCV000924252	pathogenic	Cystic fibrosis	2017-12-08	reviewed by expert panel	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007573	SCV001584167	pathogenic	Cystic fibrosis	2019-05-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CFTR protein function (PMID: 29805046, 30046002). This variant has been observed in several individuals affected with cystic fibrosis (PMID: 1284639, 9459534, 7539342, 24586523). ClinVar contains an entry for this variant (Variation ID: 7153). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 311 of the CFTR protein (p.Phe311Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine.
Institute of Reproductive Genetics, University of Münster	RCV001642201	SCV001860336	pathogenic	Obstructive azoospermia	2021-08-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007573	SCV002687390	pathogenic	Cystic fibrosis	2015-04-30	criteria provided, single submitter	clinical testing	The p.F311L pathogenic mutation (also known as c.933C>G), located in coding exon 8 of the CFTR gene, results from a C to G substitution at nucleotide position 933. The phenylalanine at codon 311 is replaced by leucine, an amino acid with highly similar properties. This mutation has been reported in multiple studies in patients who have classic CF symptoms and elevated sweat chloride levels along with a second pathogenic mutation (Ferec et al. Nat Genet.1992;1(3):188-191, Jezequel et al. Clin Chem. 1995;41(6Pt1):833-5, Scotet et al. Hum Mutat.2003;22(1):105). Another study reported a patient with chronic pancreatitis who had this mutation in cis with p.V754M and deltaF508 on the other chromosome (Niel et al. Hum Mutat. 2006;27(7):716-7). Based on the supporting evidence, p.F311L is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003473025	SCV004213433	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-08-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007573	SCV006071356	pathogenic	Cystic fibrosis	2025-03-25	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.933C>G (p.Phe311Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251140 control chromosomes (gnomAD). c.933C>G has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Fichou_2008, McCague_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 16.8% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 30888834, 38388235, 17825628). ClinVar contains an entry for this variant (Variation ID: 7153). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000007573	SCV000027774	pathogenic	Cystic fibrosis	1992-06-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000007573	SCV001456055	pathogenic	Cystic fibrosis	2020-09-16	no assertion criteria provided	clinical testing