Submissions for variant NM_000492.4(CFTR):c.2453del (p.Leu818fs)

dbSNP: rs397515498

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056364	SCV000071476	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Baylor Genetics	RCV001004477	SCV001163522	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000056364	SCV001167240	pathogenic	Cystic fibrosis	2019-10-15	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056364	SCV001623105	pathogenic	Cystic fibrosis	2021-04-26	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2453delT (p.Leu818TrpfsX3) 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 was absent in 186888 control chromosomes. c.2453delT has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Schrijver_2005, 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. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056364	SCV002122734	pathogenic	Cystic fibrosis	2022-01-20	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: 66102). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 23974870). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu818Trpfs*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).
Ambry Genetics	RCV000056364	SCV002731578	pathogenic	Cystic fibrosis	2018-08-31	criteria provided, single submitter	clinical testing	The c.2453delT pathogenic mutation (also known as 2585delT), located in coding exon 14 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 2453, causing a translational frameshift with a predicted alternate stop codon (p.L818Wfs*3). This mutation was identified in an individual with clinical symptoms of cystic fibrosis in conjunction with p.F508del (Schrijver I et al. J Mol Diagn, 2005 May;7:289-99). This pathogenic mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). 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.
Fulgent Genetics, Fulgent Genetics	RCV002496744	SCV002804667	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474640	SCV004213413	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831811	SCV002080747	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing