Submissions for variant NM_000492.4(CFTR):c.1327_1330dup (p.Ile444fs)

dbSNP: rs397508189

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000169333	SCV000071468	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224712	SCV000281544	pathogenic	not provided	2015-02-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000224712	SCV000601040	pathogenic	not provided	2017-05-22	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000224712	SCV000863370	pathogenic	not provided	2018-09-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169333	SCV001362739	pathogenic	Cystic fibrosis	2019-08-12	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1327_1330dupGATA (p.Ile444ArgfsX3) 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 2.5e-05 in 242172 control chromosomes (gnomAD). c.1327_1330dupGATA has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Zielenski_1995, 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. Four submitters, including one expert panel (CFTR2) have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169333	SCV002141489	pathogenic	Cystic fibrosis	2024-07-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile444Argfs*3) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 7537150, 23974870). This variant is also known as 1461ins4 and c.1329_1330insAGAT. ClinVar contains an entry for this variant (Variation ID: 188958). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000169333	SCV002507348	pathogenic	Cystic fibrosis	2020-02-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000169333	SCV002689089	pathogenic	Cystic fibrosis	2021-06-14	criteria provided, single submitter	clinical testing	The c.1327_1330dupGATA pathogenic mutation, located in coding exon 10 of the CFTR gene, results from a duplication of GATA at nucleotide position 1327, causing a translational frameshift with a predicted alternate stop codon (p.I444Rfs*3). This alteration has been identified in multiple individuals diagnosed with Cystic Fibrosis (Zielenski et al. Hum. Mutat. 1995 ;5(1):43-7; Brennan ML et al. J Cyst Fibros, 2016 Jan;15:52-9; Cohen JL et al. Am J Med Genet A, 2018 10;176:2203-2214). A further study of 16 patients with this pathogenic mutation determined that pulmonary disease, elevated sweat chloride levels, and pancreatic insufficiency were common features of individuals who had this alteration (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167). Of note this alteration is also described in the literature as 1461ins4 and c.1329_1330insAGAT. 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.
Fulgent Genetics, Fulgent Genetics	RCV002492691	SCV002800908	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-05-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001826867	SCV004118427	pathogenic	CFTR-related disorder	2022-09-07	criteria provided, single submitter	clinical testing	The CFTR c.1327_1330dupGATA variant is predicted to result in a frameshift and premature protein termination (p.Ile444Argfs*3). This variant has been reported as causative for cystic fibrosis (see for example Zielenski et al 1995. PubMed ID: 7537150; Sosnay PR et al 2013. PubMed ID: 23974870; Beauchamp KA et al 2019. PubMed ID: 31036917). This variant is reported in 0.0046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117188810-A-AAGAT). Frameshift variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003474906	SCV004213390	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-09-13	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000169333	SCV004244658	pathogenic	Cystic fibrosis	2023-10-26	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3
Counsyl	RCV000169333	SCV000220674	pathogenic	Cystic fibrosis	2016-09-09	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826867	SCV002080575	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001826867	SCV002507432	pathogenic	CFTR-related disorder	2020-02-07	no assertion criteria provided	clinical testing