Submissions for variant NM_000492.4(CFTR):c.948del (p.Phe316fs)

dbSNP: rs75528968

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007583	SCV000071464	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Eurofins Ntd Llc (ga)	RCV000079016	SCV000331317	pathogenic	not provided	2012-11-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000079016	SCV000601138	pathogenic	not provided	2016-12-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007583	SCV000697060	pathogenic	Cystic fibrosis	2020-07-24	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.948delT (p.Phe316LeufsX12) 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 2.4e-05 in 251272 control chromosomes (gnomAD). c.948delT has been reported in the literature, in the compound heterozygous or homozygous state, in multiple individuals affected with Cystic Fibrosis (e.g. Claustres_1992, McKone_2003, Claustres_2017, da Rosa_2018). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submitters including an expert panel (CFTR2) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000007583	SCV000885173	pathogenic	Cystic fibrosis	2024-10-01	criteria provided, single submitter	clinical testing	The CFTR c.948del; p.Phe316LeufsTer12 variant (rs75528968, ClinVar Variation ID: 7163), also known as 1078delT, is reported in the literature in multiple individuals with cystic fibrosis, including the pancreatic insufficient form (Claustres 1992, Ooi 2012, Orozco 2001, Raraigh 2022, Sosnay 2013, CFTR2 database). This variant is found in the general population with an overall allele frequency of .002% (6/251272 alleles) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ Claustres M et al. A new mutation (1078delT) in exon 7 of the CFTR gene in a southern French adult with cystic fibrosis. Genomics. 1992 Jul;13(3):907-8. PMID: 1379211. Ooi CY, Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. PMID: 22658665. Orozco L et al. XV-2c/KM-19 haplotype analysis of cystic fibrosis mutations in Mexican patients. Am J Med Genet. 2001 Aug 15;102(3):277-81. PMID: 11484207. Raraigh KS et al. Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. J Cyst Fibros. 2022 May;21(3):463-470. PMID: 34782259. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870.
Mendelics	RCV000007583	SCV000886238	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
CFTR-France	RCV000007583	SCV001169327	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000007583	SCV001180753	pathogenic	Cystic fibrosis	2022-06-14	criteria provided, single submitter	clinical testing	The c.948delT (also known as 1078delT) pathogenic mutation, located in coding exon 8 of the CFTR gene, results from a deletion of one nucleotide at position 948, causing a translational frameshift with a predicted alternate stop codon (p.F316Lfs*12). This mutation was reported in a Spanish individual with cystic fibrosis, severe pulmonary disease, pancreatic insufficiency, and elevated sweat chloride levels in conjunction with p.F508del (Claustres M et al. Genomics, 1992 Jul;13:907-8). This alteration is associated with elevated sweat chloride levels, lung disease, 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.
Myriad Genetics, Inc.	RCV000007583	SCV001193960	pathogenic	Cystic fibrosis	2019-12-04	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.948delT(aka 1078delT) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID 9259197, 1284538, 18456578, 23974870, 22658665, 24440181 and 1379211. Classification of NM_000492.3(CFTR):c.948delT(aka 1078delT) 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007583	SCV001589607	pathogenic	Cystic fibrosis	2024-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe316Leufs*12) 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 (rs775056460, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis and/or pancreatic insufficiency (PMID: 1379211, 22658665, 27738188). This variant is also known as c.1078del. ClinVar contains an entry for this variant (Variation ID: 7163). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007583	SCV002573897	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
Baylor Genetics	RCV003473030	SCV004213424	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-24	criteria provided, single submitter	clinical testing
OMIM	RCV000007583	SCV000027784	pathogenic	Cystic fibrosis	1993-12-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000079016	SCV001743254	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000079016	SCV001970893	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826437	SCV002078162	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing