Submissions for variant NM_000492.4(CFTR):c.3659del (p.Thr1220fs)

gnomAD frequency: 0.00001  dbSNP: rs121908811

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007544	SCV000071480	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Mendelics	RCV000007544	SCV000886227	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004502	SCV001163547	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007544	SCV001169299	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000007544	SCV001193907	pathogenic	Cystic fibrosis	2019-12-07	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.3659delC(T1220Kfs*8, aka 3791delC) 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. Classification of NM_000492.3(CFTR):c.3659delC(T1220Kfs*8, aka 3791delC) 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000007544	SCV001425440	pathogenic	Cystic fibrosis	2020-02-24	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007544	SCV001442633	pathogenic	Cystic fibrosis	2020-10-12	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3659delC (p.Thr1220LysfsX8) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250166 control chromosomes. c.3659delC has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007544	SCV002228111	pathogenic	Cystic fibrosis	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1220Lysfs*8) 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 (rs121908811, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 9150159, 23261175, 23974870). This variant is also known as c.3791delC. ClinVar contains an entry for this variant (Variation ID: 7124). 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.
Ambry Genetics	RCV000007544	SCV002613471	pathogenic	Cystic fibrosis	2022-07-26	criteria provided, single submitter	clinical testing	The c.3659delC pathogenic mutation, located in coding exon 22 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 3659, causing a translational frameshift with a predicted alternate stop codon (p.T1220Kfs*8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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 07/26/2022). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003473011	SCV004213360	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-13	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV004558238	SCV005046900	pathogenic	not provided	2022-07-26	criteria provided, single submitter	clinical testing
OMIM	RCV000007544	SCV000027745	pathogenic	Cystic fibrosis	1990-11-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001831526	SCV002075859	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing