Submissions for variant NM_000492.4(CFTR):c.658C>T (p.Gln220Ter)

dbSNP: rs397508778

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056401	SCV000071544	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Mendelics	RCV000056401	SCV000886230	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763566	SCV000894405	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004236	SCV001163112	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056401	SCV001169335	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056401	SCV001362674	pathogenic	Cystic fibrosis	2019-05-28	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.658C>T (p.Gln220X) 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 (c.803delA, p.Asn268fsX17; c.850dupA, p.Met284fsX3; c.948delT, p.Phe316LeufsX12). The variant allele was found at a frequency of 4e-06 in 251438 control chromosomes (gnomAD). The variant, c.658C>T, has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Koh_2006, Tomaiuolo_2010, Ooi_2012, Sosonay_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. One publication, Sosnay_2013, reports that spliced RNA product is less than 10% of WT level predicted by NMD (nonsense mediated decay). Three ClinVar submissions including one expert panel (CFTR2) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056401	SCV001580630	pathogenic	Cystic fibrosis	2023-08-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54036). This premature translational stop signal has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 7515303, 16778407). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs397508778, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln220*) 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).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000056401	SCV002573890	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	RCV000056401	SCV002664680	pathogenic	Cystic fibrosis	2020-06-17	criteria provided, single submitter	clinical testing	The p.Q220* pathogenic mutation (also known as c.658C>T), located in coding exon 6 of the CFTR gene, results from a C to T substitution at nucleotide position 658. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This mutation was described in trans with a second pathogenic mutation in an individual presenting with respiratory symptoms, bronchiectasis, and elevated sweat chloride levels (Koh WJ et al. J Korean Med Sci. 2006;21(3):563-6). In addition to pulmonary symptoms and elevated sweat chloride levels, this mutation is also associated with pancreatic insufficiency (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.
Baylor Genetics	RCV003474614	SCV004213313	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-02-22	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000056401	SCV004239101	pathogenic	Cystic fibrosis	2023-07-26	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Counsyl	RCV000056401	SCV001132351	pathogenic	Cystic fibrosis	2014-01-02	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826695	SCV002078124	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing