Submissions for variant NM_000492.4(CFTR):c.2125C>T (p.Arg709Ter)

gnomAD frequency: 0.00001  dbSNP: rs121908760

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056359	SCV000071553	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056359	SCV000696887	pathogenic	Cystic fibrosis	2017-06-23	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.2125C>T (p.Arg709X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.3266G>A/p.Trp1089X, c.3276C>A/p.Tyr1092X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/119868 control chromosomes at a frequency of 0.0000167, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant has been reported in multiple CF patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000727640	SCV000854925	pathogenic	not provided	2018-05-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000056359	SCV000886260	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000727640	SCV001134125	pathogenic	not provided	2018-11-14	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 symptomatic patient, and found in general population data at a frequency consistent with pathogenicity. Occurs in multiple cases with a recessive pathogenic variant in the same gene.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000919	SCV001158006	pathogenic	not specified	2018-11-20	criteria provided, single submitter	clinical testing	The CFTR c.2125C>T; p.Arg709Ter variant (rs121908760) is reported in the literature in multiple individuals affected with pancreatic insufficient cystic fibrosis (Sosnay 2013, CFTR2 database, ABCC7 Mutation database and references therein). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 53440), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), 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, the p.Arg709Ter variant is considered to be pathogenic. References: Link to CFTR2 database: https://cftr2.org/mutation/scientific/pi/R709X Link to ABCC7 (CFTR) Mutation database: http://abcmutations.hegelab.org/mutationDetails?id=4542 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.
Baylor Genetics	RCV001004468	SCV001163513	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056359	SCV001169540	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000056359	SCV001193956	pathogenic	Cystic fibrosis	2019-12-04	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.2125C>T(R709*) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 23974870, 7535742 and 22658665. Classification of NM_000492.3(CFTR):c.2125C>T(R709*) 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056359	SCV001588678	pathogenic	Cystic fibrosis	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg709*) 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 (rs121908760, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 7535742, 9482579, 20059485, 23974870). ClinVar contains an entry for this variant (Variation ID: 53440). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000056359	SCV002072897	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing	The stop gained p.R709Ter in CFTR (NM_000492.3) has been previously reported in pancreatic insufficient cystic fibrosis patients (Sosnay PR et al). It has been classified as a Pathogenic mutation by the ClinVar expert panel. It has been submitted to ClinVar as Pathogenic. The p.R709Ter variant is observed in 4/30,772 (0.0130%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000727640	SCV002502614	pathogenic	not provided	2022-03-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000727640	SCV002525777	pathogenic	not provided	2021-07-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000056359	SCV002726087	pathogenic	Cystic fibrosis	2022-07-06	criteria provided, single submitter	clinical testing	The p.R709* pathogenic mutation (also known as c.2125C>T), located in coding exon 14 of the CFTR gene, results from a C to T substitution at nucleotide position 2125. This changes the amino acid from an arginine to a stop codon within coding exon 14. This mutation was first described in an individual with pancreatic sufficient cystic fibrosis, who was compound heterozygous for p.F508del (Bonizzato A et al. Hum. Genet., 1995 Apr;95:397-402). This mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and an increased rate of Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). 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	RCV003473476	SCV004213309	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826631	SCV002080709	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing