Submissions for variant NM_000492.4(CFTR):c.4251del (p.Glu1418fs)

dbSNP: rs397508706

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056391	SCV000071486	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056391	SCV000075132	pathogenic	Cystic fibrosis	2024-06-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1418Argfs*14) in the CFTR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 63 amino acid(s) of the CFTR protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with classic symptoms of Cystic Fibrosis (PMID: 7691344, 15638824, 23974870; www.CFTR2.org). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53933). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056391	SCV000697019	pathogenic	Cystic fibrosis	2017-06-13	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.4251delA (p.Glu1418Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR 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 (e.g. c.4364C>G, p.Ser1455X; c.4426C>T, p.Gln1476X). One in silico tool predicts a damaging outcome for this variant. The variant of interest has not been found in a large, broad control population, ExAC in 120796 control chromosomes. This variant was found in multiple CF patients with mean sweat chloride conc 60mM (Sosnay_Nature Genetics_2013) including in a patient in compound heterozigosity with c.3849+1G>A (not in our internal database) with a presentation characteristic of Pseudo-Bartters syndrome, a rare typical presentation of CF (Nahida_ActaPed_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, including CFTR2 where it was reported in 62 patients, with an average of 103 mEq/L sweat chloride, (33% with PI, 40% with Pseudomonas infection). Taken together, this variant is classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000727667	SCV000854976	pathogenic	not provided	2017-10-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002184	SCV001160055	pathogenic	not specified	2018-10-21	criteria provided, single submitter	clinical testing	The CFTR c.4251delA; p.Glu1418fs variant (rs397508706), also known as 4382delA, is reported in the literature in multiple individuals affected with cystic fibrosis, including in a compound heterozygous state with a known pathogenic CFTR allele (Castaldo 2005, Claustres 1993, Nahida 2011, Sermet-Gaudelus 2010, Sosnay 2013). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 53933), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the CFTR gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein that would include a sequence of 14 amino acid residues not usually present. Based on available information, the p.Glu1418fs variant is considered to be pathogenic. References: Castaldo G et al. Comprehensive cystic fibrosis mutation epidemiology and haplotype characterization in a southern Italian population. Ann Hum Genet. 2005 Jan;69(Pt 1):15-24. Claustres M et al. Analysis of the 27 exons and flanking regions of the cystic fibrosis gene: 40 different mutations account for 91.2% of the mutant alleles in southern France. Hum Mol Genet. 1993 Aug;2(8):1209-13. Nahida el-R et al. Pseudo-Bartter's syndrome revealing cystic fibrosis in an infant caused by 3849 + 1G>A and 4382delA compound heterozygosity. Acta Paediatr. 2011 Nov;100(11):e234-5. Sermet-Gaudelus I et al. Measurement of nasal potential difference in young children with an equivocal sweat test following newborn screening for cystic fibrosis. Thorax. 2010 Jun;65(6):539-44. Sosnay PR Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7.
CFTR-France	RCV000056391	SCV001169387	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000727667	SCV001714848	pathogenic	not provided	2020-01-20	criteria provided, single submitter	clinical testing	PVS1_strong, PM2, PS3, PM3, PP5
Mendelics	RCV002247438	SCV002518692	pathogenic	Hereditary pancreatitis	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000056391	SCV004085785	pathogenic	Cystic fibrosis	2023-08-22	criteria provided, single submitter	clinical testing	The c.4251delA pathogenic mutation (also known as 4382delA), located in coding exon 27 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 4251, causing a translational frameshift with a predicted alternate stop codon (p.E1418Rfs*14). This alteration occurs at the 3' terminus of the CFTR gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 63 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been reported in multiple individuals with cystic fibrosis and elevated sweat chloride levels (Claustres M et al. Hum. Mol. Genet., 1993 Aug;2:1209-13; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003474602	SCV004213293	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000727667	SCV004234594	pathogenic	not provided	2022-10-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826685	SCV002075959	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing