Submissions for variant NM_000492.4(CFTR):c.2875del (p.Ala959fs)

dbSNP: rs397508447

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056373	SCV000071478	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000056373	SCV000220800	likely pathogenic	Cystic fibrosis	2014-10-14	criteria provided, single submitter	literature only
Illumina Laboratory Services, Illumina	RCV000056373	SCV000916184	pathogenic	Cystic fibrosis	2018-11-02	criteria provided, single submitter	clinical testing	The CFTR c.2875delG (p.Ala959HisfsTer9) variant, also referred to in the literature as c.3007delG, results in a frameshift and a premature truncation of the protein. This variant is widely reported in the literature and is classified as a cystic fibrosis (CF)-causing mutation according to the CFTR2 mutation database (www.cftr2.org). The database states the mutation has been observed in 40 CF individuals. Across a selection of the available literature, the p.Ala959HisfsTer9 variant was found in three compound heterozygous CF probands, in seven heterozygous probands with CF or congenital bilateral absence of vas deferens (CBAVD) and in 31 additional proband alleles (Mercier et al. 1994; Claustres et al. 2000; Scotet et al. 2003; des Georges et al. 2004; Dorfman et al. 2010; Sosnay et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project but this is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. Based on the collective evidence and the potential impact of frameshift variants, the p.Ala959HisfsTer9 variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781227	SCV000919131	pathogenic	not specified	2018-07-31	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2875delG (p.Ala959HisfsX9) 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 (e.g., p.Trp1089X, p.Tyr1092X). The variant allele was found at a frequency of 4.1e-06 in 246118 control chromosomes. c.2875delG has been reported in the literature in multiple individuals affected with Cystic Fibrosis. These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985685	SCV001134131	pathogenic	not provided	2019-04-13	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
CFTR-France	RCV000056373	SCV001169524	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Johns Hopkins Genomics, Johns Hopkins University	RCV000056373	SCV001425419	pathogenic	Cystic fibrosis	2020-04-22	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056373	SCV002230780	pathogenic	Cystic fibrosis	2024-11-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala959Hisfs*9) 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 (rs397508447, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 23974870). ClinVar contains an entry for this variant (Variation ID: 53583). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000056373	SCV002573833	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
Ambry Genetics	RCV000056373	SCV005107472	pathogenic	Cystic fibrosis	2024-04-11	criteria provided, single submitter	clinical testing	The c.2875delG pathogenic mutation, located in coding exon 17 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 2875, causing a translational frameshift with a predicted alternate stop codon (p.A959Hfs*9). This alteration is associated with elevated sweat chloride levels, decreased lung function, pancreatic insufficiency, and Pseudomonas infection (Sosnay PR, Nat. Genet. 2013 Oct; 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.
Natera, Inc.	RCV001831759	SCV002083553	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing