Submissions for variant NM_000492.4(CFTR):c.223C>T (p.Arg75Ter)

gnomAD frequency: 0.00001  dbSNP: rs121908749

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056362	SCV000071554	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Baylor Genetics	RCV001004232	SCV001163108	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056362	SCV001169536	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000056362	SCV001194207	pathogenic	Cystic fibrosis	2019-12-09	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.223C>T(R75*) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID 7541274, 23420618, 7525450, 9806422, 22658665 and 23974870. Classification of NM_000492.3(CFTR):c.223C>T(R75*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284476	SCV001470291	pathogenic	not provided	2019-10-16	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001284476	SCV001474367	pathogenic	not provided	2023-11-20	criteria provided, single submitter	clinical testing	The CFTR c.223C>T; p.Arg75Ter variant (rs121908749) is reported in the literature in individuals affected with cystic fibrosis (Dork 1994, Sosnay 2013, CFTR2 database). This variant has been observed in affected individuals in trans to another pathogenic variant (Dork 1994) and the majority of patients described exhibit elevated sweat chloride and pancreatic insufficiency (Sosnay 2013, CFTR2 database). This variant is found on only six chromosomes (6/250976 alleles) in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org Dork T et al. Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients. Hum Genet. 1994 Nov;94(5):533-42. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056362	SCV001587414	pathogenic	Cystic fibrosis	2024-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg75*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs121908749, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with CF and cystic fibrosis (CF) (PMID: 7525450, 10923036, 18456578, 22658665, 22975760, 23276700, 23523379, 23974870, 26014425, 26574590). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 48672). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000056362	SCV001711952	pathogenic	Cystic fibrosis	2021-05-25	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Revvity Omics, Revvity	RCV001284476	SCV002019235	pathogenic	not provided	2022-08-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000056362	SCV002507351	pathogenic	Cystic fibrosis	2022-02-25	criteria provided, single submitter	clinical testing
Arcensus	RCV000056362	SCV002564622	likely pathogenic	Cystic fibrosis	2013-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000056362	SCV002727956	pathogenic	Cystic fibrosis	2025-01-22	criteria provided, single submitter	clinical testing	The p.R75* pathogenic mutation (also known as c.223C>T), located in coding exon 3 of the CFTR gene, results from a C to T substitution at nucleotide position 223. This changes the amino acid at codon 75 from arginine to a stop codon. This mutation was first described in a pancreatic insufficient German individual who was confirmed to have p.N1303K in trans (Dork T et al. Hum Genet. 1994;94(5):533-542). This mutation has pan-ethnic distribution (Rohlfs EM et al. Clin Chem. 2011;57(6):841-8) and is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 10/25/2021). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003473290	SCV004213297	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-17	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000056362	SCV004806960	pathogenic	Cystic fibrosis	2024-03-26	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000056362	SCV005042894	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing	The stop-gained variant c.223C>T p.Arg75Ter in the CFTR gene has been reported in the hemizygous and heterozygous state in multiple individuals affected with Cystic Fibrosis Guo et al., 2021; Singh et al., 2015. This variant is reported with the allele frequency 0.0007% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It has been submitted to ClinVar as Likely Pathogenic/ Pathogenic Multiple Submissions. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001284476	SCV005046905	pathogenic	not provided	2022-11-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031482	SCV005673791	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-03-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831710	SCV002080089	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001831710	SCV002507435	pathogenic	CFTR-related disorder	2022-02-25	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001831710	SCV004118211	pathogenic	CFTR-related disorder	2024-04-10	no assertion criteria provided	clinical testing	The CFTR c.223C>T variant is predicted to result in premature protein termination (p.Arg75*). This variant has been reported in multiple individuals with cystic fibrosis with and without pancreatic insufficiency (see for example, Doerk et al. 1994. PubMed ID: 7525450; Wong et al. 2001. PubMed ID: 11668613; Ooi et al. 2012. PubMed ID: 22658665; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.