Submissions for variant NM_000492.4(CFTR):c.1466C>A (p.Ser489Ter)

gnomAD frequency: 0.00003  dbSNP: rs397508211

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056349	SCV000071559	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000056349	SCV000486831	pathogenic	Cystic fibrosis	2016-08-18	criteria provided, single submitter	clinical testing
CFTR-France	RCV000056349	SCV001169483	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056349	SCV001585580	pathogenic	Cystic fibrosis	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser489*) 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 (rs397508211, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 21520337, 22627569, 23974870). ClinVar contains an entry for this variant (Variation ID: 53259). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000056349	SCV002507323	pathogenic	Cystic fibrosis	2019-07-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000056349	SCV002698807	pathogenic	Cystic fibrosis	2022-06-13	criteria provided, single submitter	clinical testing	The p.S489* pathogenic mutation (also known as c.1466C>A), located in coding exon 11 of the CFTR gene, results from a C to A substitution at nucleotide position 1466. This changes the amino acid from a serine to a stop codon within coding exon 11. In one study, this mutation was described as compound heterozygous in 12 individuals with another pathogenic mutation and as homozygous in one individual all with classic cystic fibrosis (De Bie I et al. Genet Med. 2012;14(10):883-886). This mutation has also been observed in an individual with congenital bilateral absence of the vas deferens (Steiner B et al. Hum Mutat. 2011;32(8):912-20). Affected individuals carrying this pathogenic mutation had elevated sweat chloride levels, pancreatic insufficiency, and higher rates of Pseduomonas infection (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167 and The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed June 13, 2022). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056349	SCV004020649	pathogenic	Cystic fibrosis	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1466C>A (p.Ser489X) 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 4e-06 in 251332 control chromosomes. c.1466C>A has been reported in the literature in a homozygous individual and multiple compound heterozygous individuals affected with Cystic Fibrosis (Example: DeBie_2012). 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 publication have been ascertained in the context of this evaluation (PMID: 22627569). Seven 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.
Baylor Genetics	RCV003473456	SCV004213493	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-02-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005042128	SCV005673322	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-05-20	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528800	SCV001741170	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528800	SCV001972411	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831728	SCV002080600	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001831728	SCV002507407	pathogenic	CFTR-related disorder	2019-07-23	no assertion criteria provided	clinical testing