Submissions for variant NM_000492.4(CFTR):c.2490+1G>A

dbSNP: rs141158996

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007595	SCV000071455	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007595	SCV000074614	pathogenic	Cystic fibrosis	2024-07-13	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 14 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs141158996, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 7683952, 9239681, 12815607, 20059485, 23974870). This variant is also known as 2622+1G>A. ClinVar contains an entry for this variant (Variation ID: 7175). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007595	SCV000696902	pathogenic	Cystic fibrosis	2016-06-07	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.2490+1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant, and 5/5 splicing algorithms predict the variant to abolish the canonical splice donor site. This variant was found in 2/109598 control chromosomes at a frequency of 0.0000182, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been cited in numerous classic CF patients in the literature in trans with pathogenic variants, including deltaF508. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
CFTR-France	RCV000007595	SCV001169549	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000007595	SCV001176547	pathogenic	Cystic fibrosis	2022-07-18	criteria provided, single submitter	clinical testing	The c.2490+1G>A intronic pathogenic mutation (also known as 2622+1G>A) results from a G to A one nucleotide after coding exon 14 of the CFTR gene. This mutation was first described in an affected two-year-old with cystic fibrosis, including pancreatic insufficiency and pulmonary disease, in conjunction with p.F508del (Audrézet MP et al. Hum. Mol. Genet., 1993 Jan;2:51-4). This mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and an increased rate of Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000007595	SCV001477844	pathogenic	Cystic fibrosis	2023-12-21	criteria provided, single submitter	clinical testing	The CFTR c.2490+1G>A variant (rs141158996), also known as 2622+1G>A, has been identified in many individuals affected with pancreatic insufficient forms of cystic fibrosis (see link for CFTR2 database, Audrezet 1993, Dorfman 2010, Krenkova 2013, Scotet 2003, Sosnay 2013) and at least one individual with congenital bilateral absence of the vas deferens (De Braekeleer 1996). This variant is also reported in ClinVar (Variation ID: 7175). This variant disrupts the canonical splice donor site of intron 13, which is likely to negatively impact gene function. Based on available information, this variant is considered pathogenic. References: Link to CFTR2 database: https://cftr2.org/ Audrezet M et al. Identification of 12 novel mutations in the CFTR gene. Hum Mol Genet. 1993 Jan;2(1):51-4. PMID: 7683952. De Braekeleer M et al. Mutations in the cystic fibrosis gene in men with congenital bilateral absence of the vas deferens. Mol Hum Reprod. 1996 Sep;2(9):669-77. PMID: 9239681. Dorfman R et al. Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? Clin Genet. 2010 May;77(5):464-73. PMID: 20059485. Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. PMID: 23276700. Scotet V et al. Comparison of the CFTR mutation spectrum in three cohorts of patients of Celtic origin from Brittany (France) and Ireland. Hum Mutat. 2003 Jul;22(1):105. PMID: 12815607. Sosnay P 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509317	SCV001715951	pathogenic	not provided	2024-07-16	criteria provided, single submitter	clinical testing	PP3, PM2, PM3_very_strong, PVS1
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000007595	SCV002507345	pathogenic	Cystic fibrosis	2019-07-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031413	SCV005673360	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-03-13	criteria provided, single submitter	clinical testing
OMIM	RCV000007595	SCV000027796	pathogenic	Cystic fibrosis	2018-04-09	no assertion criteria provided	literature only
Counsyl	RCV000007595	SCV000220959	pathogenic	Cystic fibrosis	2015-07-21	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826439	SCV002080756	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001826439	SCV002507429	pathogenic	CFTR-related disorder	2019-07-31	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001826439	SCV005363185	pathogenic	CFTR-related disorder	2024-03-20	no assertion criteria provided	clinical testing	The CFTR c.2490+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also known as c.2622+1G>A, has been repeatedly documented as pathogenic in individuals with cystic fibrosis (Audrezet et al. 1993. PubMed ID: 7683952; Scotet et al. 2003. PubMed ID: 12815607; Sosnay et al. 2013, PubMed ID: 23974870; https://cftr2.org/mutation/scientific/2622%252B1G-%253EA). Multiple clinical diagnostic labs have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/7175/). This variant is reported in 0.0021% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.