Submissions for variant NM_000492.4(CFTR):c.3873+2T>C

dbSNP: rs146795445

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000576323	SCV000677607	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000576323	SCV000696984	pathogenic	Cystic fibrosis	2016-11-09	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.3873+2T>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the loss of a canonical splice donor site. This variant was found in 1/118992 control chromosomes at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in numerous affected individuals in the literature, both pancreatic sufficient and insufficient patients. Taken together, this variant is classified as pathogenic.
Counsyl	RCV000576323	SCV000792802	pathogenic	Cystic fibrosis	2017-07-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576323	SCV001580626	pathogenic	Cystic fibrosis	2024-12-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 23 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 (rs146795445, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 19318346, 26348465). ClinVar contains an entry for this variant (Variation ID: 53828). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507715	SCV001713439	pathogenic	not provided	2020-01-27	criteria provided, single submitter	clinical testing	PVS1, PM2, PP3, PP4, PP5
Institute of Human Genetics, University of Leipzig Medical Center	RCV000576323	SCV002574086	likely 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_STR, PM2_SUP, PM3_STR
Ambry Genetics	RCV000576323	SCV002622431	pathogenic	Cystic fibrosis	2022-04-06	criteria provided, single submitter	clinical testing	The c.3873+2T>C intronic pathogenic mutation (also known as 4005+2T>C) results from a T to C substitution two nucleotides after coding exon 23 in the CFTR gene. This mutation was identified in a Norwegian infant with elevated sweat chloride levels in conjunction with p.F508del; however, the phase was not confirmed (Lundman E et al. J. Cyst. Fibros., 2016 May;15:318-24). This alteration is one of the most commonly reported mutations in Norwegian individuals with cystic fibrosis, accounting for 3.8% of alleles in that population (Munthe-Kaas MC et al. Respir Med, 2006 Dec;100:2121-8). 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.
Natera, Inc.	RCV001831780	SCV002075897	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing