Submissions for variant NM_000492.4(CFTR):c.3472C>T (p.Arg1158Ter)

gnomAD frequency: 0.00002  dbSNP: rs79850223

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007564	SCV000071550	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
GeneDx	RCV000579152	SCV000680709	pathogenic	not provided	2017-06-16	criteria provided, single submitter	clinical testing	The R1158X variant in the CFTR gene has been reported previously in association with cystic fibrosis (Ronchetto et al., 1992; Frossard et al., 2000; Ooi et al., 2012; Sosnay et al., 2013). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1158X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R1158X as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007564	SCV000696972	pathogenic	Cystic fibrosis	2016-09-28	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.3472C>T (p.Arg1158X) 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 in CF or CFTR-related diseases. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg1162X, p.Gln1382X, p.Ser1455X, etc.). This variant was found in 5/120064 control chromosomes at a frequency of 0.0000416, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant has been reported in many affected individuals with CF and CF-RDs (Amato_2012, Sosnay_2013). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000579152	SCV000883575	pathogenic	not provided	2017-10-04	criteria provided, single submitter	clinical testing	The CFTR c.3472C>T; p.Arg1158Ter variant is reported in the medical literature in individuals with cystic fibrosis and related disorders (Amato 2012, Frossard 2000, Ooi 2012, Sosnay 2013). The variant is listed in the ClinVar database (Variation ID: 7144), in the dbSNP variant database (rs79850223), and in the Genome Aggregation Database with a low population frequency (8/245236 alleles). This variant introduces a premature termination codon and is predicted to result in a truncated protein or mRNA subject to non-sense mediated decay. Considering available information, this variant is classified as severely pathogenic. References: Amato F et al. Extensive molecular analysis of patients bearing CFTR-related disorders. J Mol Diagn. 2012 Jan;14(1):81-9. Frossard PM et al. Mild clinical phenotype associated with R1158X/S549R(T-->G) CFTR genotype. Clin Genet. 2000 Aug;58(2):147-9. Ooi CY and Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. 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.
Mendelics	RCV000007564	SCV000886237	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763158	SCV000893745	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-10-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004499	SCV001163544	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007564	SCV001169264	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000007564	SCV001181859	pathogenic	Cystic fibrosis	2022-07-06	criteria provided, single submitter	clinical testing	The p.R1158* pathogenic mutation (also known as c.3472C>T) is located in coding exon 22 of the CFTR gene. This alteration results from a C to T substitution at nucleotide position 3472. The arginine at codon 1158 is replaced by a stop codon within coding exon 22. This alteration has been reported in individuals with cystic fibrosis (Ronchetto P et al. Genomics. 1992;12(2):417-418; Castaldo G et al. Clin Chem. 1999;45(7):957-962; Frossard et al. Clin Genet. 2000;58:147-9; Sosnay PR et al. Nat Genet. 2013;45(10):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.
Myriad Genetics, Inc.	RCV000007564	SCV001194162	pathogenic	Cystic fibrosis	2019-11-11	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.3472C>T(R1158*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870 and 21909392. Classification of NM_000492.3(CFTR):c.3472C>T(R1158*) 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.‚Äã
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000579152	SCV001470497	pathogenic	not provided	2020-08-10	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 found in general population data at a frequency that is consistent with pathogenicity.
Invitae	RCV000007564	SCV001583912	pathogenic	Cystic fibrosis	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1158*) 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 (rs79850223, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis and/or congenital bilateral absence of the vas deferens (PMID: 22020151, 22658665, 23974870). ClinVar contains an entry for this variant (Variation ID: 7144). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415673	SCV004115758	pathogenic	CFTR-related condition	2022-10-06	criteria provided, single submitter	clinical testing	The CFTR c.3472C>T variant is predicted to result in premature protein termination (p.Arg1158*). This variant has been reported in many unrelated individuals to be causative for cystic fibrosis and CFTR-related diseases (Ronchetto et al.1992. PubMed ID: 1371265; Frossard et al. 2000. PubMed ID: 11005149; Amato et al. 2012. PubMed ID: 22020151; Ooi et al. 2012. PubMed ID: 22658665; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117267579-C-T). Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003473022	SCV004213357	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-09-27	criteria provided, single submitter	clinical testing
OMIM	RCV000007564	SCV000027765	pathogenic	Cystic fibrosis	1992-02-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000579152	SCV001740838	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000579152	SCV001956281	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000579152	SCV001965136	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831535	SCV002075833	pathogenic	CFTR-related disorders	2017-03-17	no assertion criteria provided	clinical testing