Submissions for variant NM_000492.4(CFTR):c.1021_1022dup (p.Phe342fs)

dbSNP: rs387906360

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007554	SCV000071465	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Eurofins Ntd Llc (ga)	RCV000723429	SCV000232558	pathogenic	not provided	2014-07-10	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000007554	SCV000584078	pathogenic	Cystic fibrosis	2015-06-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007554	SCV000917217	pathogenic	Cystic fibrosis	2025-03-05	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1021_1022dupTC (p.Phe342HisfsX28) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.8e-05 in 251226 control chromosomes (gnomAD). c.1021_1022dupTC has been reported in the literature in numerous individuals affected with Cystic Fibrosis (e.g. Iannuzzi_1991, Friedman_1995, Pignatti_1995, Ahmed_2003, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12865275, 7550243, 1990834, 7543317, 23974870). ClinVar contains an entry for this variant (Variation ID: 7134). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001004249	SCV001163125	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000723429	SCV001450366	pathogenic	not provided	2017-06-15	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000007554	SCV001573148	pathogenic	Cystic fibrosis	2021-04-23	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007554	SCV001590784	pathogenic	Cystic fibrosis	2024-06-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe342Hisfs*28) 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 (rs751437088, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with Cystic Fibrosis (CF) (PMID: 1990834, 12865275, 23974870; Invitae). This variant is also known as 1154insTC. ClinVar contains an entry for this variant (Variation ID: 7134). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000723429	SCV001714228	pathogenic	not provided	2022-06-28	criteria provided, single submitter	clinical testing	PP5, PM2, PVS1
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000723429	SCV002046184	pathogenic	not provided	2021-02-09	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of CFTR protein synthesis. In addition, it has been reported in individuals affected with Cystic Fibrosis in the published literature (PMID: 7550243 (1995), 26708955 (2016), 23974870 (2013), 22658665 (2012), 1990834 (1991), 12865275 (2003)). Therefore, the variant is classified as pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000007554	SCV002507319	pathogenic	Cystic fibrosis	2019-07-09	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007554	SCV002573797	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient 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: PVS1, PM2_SUP, PM3_VSTR, PP4
Ambry Genetics	RCV000007554	SCV002673850	pathogenic	Cystic fibrosis	2021-12-01	criteria provided, single submitter	clinical testing	The c.1021_1022dupTC pathogenic mutation, located in coding exon 8 of the CFTR gene, results from a duplication of TC at nucleotide position 1021, causing a translational frameshift with a predicted alternate stop codon (p.F342Hfs*28). This pathogenic mutation was reported to account for 0.5% of 1,238 predominantly American Caucasian cystic fibrosis (CF) chromosomes (Friedman KJ et al. Hum. Mutat., 1995;6:95-6). In another study, this mutation was reportedly detected in trans with p.F508del in two unrelated individuals with elevated sweat chloride levels, pancreatic insufficiency, and poor growth (Alper OM et al. Am. J. Med. Genet. A, 2003 Jul;120A:294-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also known as c.1154_1155insTC, 1154insTC, and c.1022_1023insTC in published literature. 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	RCV003473014	SCV004213254	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031408	SCV005673309	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-06-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000007554	SCV005878507	pathogenic	Cystic fibrosis	2024-08-08	criteria provided, single submitter	clinical testing	The CFTR c.1021_1022dupTC, p.Phe342fs variant (rs387906360, ClinVar Variation ID: 7134), also known as 1154insTC, has been reported in-trans with a pathogenic CFTR variant in multiple cystic fibrosis patients and is often associated with pancreatic insufficiency (Alper 2003, Friedman 1995, Iannuzzi 1991, Ooi 2012, Sosnay 2013, CFTR2 database). This variant is found in the non-Finnish European population with an allele frequency of 0.005% (7/128980 alleles) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by inserting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the variant is classified as pathogenic. References: CFTR2 database: http://cftr2.org/ Alper O et al. 1154insTC is not a rare CFTR mutation. Am J Med Genet A. 2003; 120A(2):294-5. PMID: 12833419 Friedman K et al. Relatively high prevalence of the CFTR mutations, G85E and 1154insTC. Hum Mutat. 1995; 6(1):95-6. PMID: 7550243 Iannuzzi M et al. Two frameshift mutations in the cystic fibrosis gene. Am J Hum Genet. 1991; 48(2):227-31. PMID: 1990834 Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. PMID: 22658665 Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870
OMIM	RCV000007554	SCV000027755	pathogenic	Cystic fibrosis	2003-07-15	no assertion criteria provided	literature only
Counsyl	RCV000007554	SCV000220355	pathogenic	Cystic fibrosis	2015-10-09	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831528	SCV002078182	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001831528	SCV002507403	pathogenic	CFTR-related disorder	2019-07-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001831528	SCV004112652	pathogenic	CFTR-related disorder	2024-07-24	no assertion criteria provided	clinical testing	The CFTR c.1021_1022dupTC variant is predicted to result in a frameshift and premature protein termination (p.Phe342Hisfs*28). This variant has been reported to be causative for cystic fibrosis and cystic fibrosis with pancreatic insufficiency (reported as c.1154insTC, Iannuzzi et al., 1991. PubMed ID: 1990834; Table S2, Sosnay et al. 2013. PubMed ID: 23974870; Ooi and Durie. 2012. PubMed ID: 22658665). Frameshift variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.