Submissions for variant NM_000492.4(CFTR):c.3230T>C (p.Leu1077Pro)

gnomAD frequency: 0.00001  dbSNP: rs139304906

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056377	SCV000071507	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056377	SCV000696959	pathogenic	Cystic fibrosis	2016-08-30	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.3230T>C (p.Leu1077Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/120564 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in numerous affected individuals in the literature and has been shown via in vitro functional studies to result in the complete loss of chloride transport/conduction (Van Goor_2013, Sosnay_2013). In addition, one clinical diagnostic laboratory/reputable database has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics	RCV000056377	SCV000886204	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004303	SCV001163180	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056377	SCV001169273	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000056377	SCV001180669	pathogenic	Cystic fibrosis	2022-07-18	criteria provided, single submitter	clinical testing	The p.L1077P pathogenic mutation (also known as c.3230T>C), located in coding exon 20 of the CFTR gene, results from a T to C substitution at nucleotide position 3230. The leucine at codon 1077 is replaced by proline, an amino acid with similar properties. In one study, this mutation was identified in one individual with cystic fibrosis in conjunction with p.F508del (Bozon D et al. Hum. Mutat., 1994;3:330-2). In another study, this mutation was seen in 4 individuals with cystic fibrosis in conjunction with a second pathogenic mutation (Parisi GF et al. BMC Res Notes, 2013 Nov;6:461). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency; in vitro functional studies showed this mutation results in no to very little chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Johns Hopkins Genomics, Johns Hopkins University	RCV000056377	SCV001431519	pathogenic	Cystic fibrosis	2020-08-20	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056377	SCV001582953	pathogenic	Cystic fibrosis	2023-07-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1077 of the CFTR protein (p.Leu1077Pro). This variant is present in population databases (rs139304906, gnomAD 0.0009%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 7517268, 17662673, 23974870, 24225052). ClinVar contains an entry for this variant (Variation ID: 53690). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 23974870).
Mayo Clinic Laboratories, Mayo Clinic	RCV001508221	SCV001714246	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing	PS3, PM3, PM2, PP3, PP5
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000056377	SCV002507322	pathogenic	Cystic fibrosis	2019-07-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000056377	SCV002573794	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 2 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_VSTR, PP3, PP4
Baylor Genetics	RCV003474572	SCV004213329	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-02-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031508	SCV005666409	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-04-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000056377	SCV001132355	pathogenic	Cystic fibrosis	2015-03-30	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826661	SCV002083616	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001826661	SCV002507406	pathogenic	CFTR-related disorder	2019-07-23	no assertion criteria provided	clinical testing