Submissions for variant NM_000492.4(CFTR):c.3874-4522A>G

gnomAD frequency: 0.00004  dbSNP: rs895394181

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000597152	SCV000705855	uncertain significance	not provided	2017-01-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000665784	SCV000789957	uncertain significance	Cystic fibrosis	2017-02-28	criteria provided, single submitter	clinical testing
CFTR-France	RCV001009398	SCV001169251	pathogenic	Cystic fibrosis; CFTR-related disorder	2018-01-29	criteria provided, single submitter	curation	when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Invitae	RCV000665784	SCV001589605	pathogenic	Cystic fibrosis	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 23 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cystic fibrosis (PMID: 21909392, 30389601). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 4005+5727A>G. ClinVar contains an entry for this variant (Variation ID: 500071). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30389601). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000597152	SCV001988688	likely pathogenic	not provided	2023-04-27	criteria provided, single submitter	clinical testing	Observed multiple times with a second CFTR causing variant in patients with cystic fibrosis or CFTR-related disorders, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Roth et al., 2011, Claustres et al., 2017); No data available from control populations to assess the frequency of this variant; Also known as 4005 + 5727A>G; This variant is associated with the following publications: (PMID: 25569440, 30389601, 31845523, 32017858, 35850704, 36349818, 21909392, 35858753)
CeGaT Center for Human Genetics Tuebingen	RCV000597152	SCV002062782	pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000665784	SCV002570339	pathogenic	Cystic fibrosis	2022-07-23	criteria provided, single submitter	clinical testing	CFTR c.3874-4522A>G has been identified in multiple individuals with features of cystic fibrosis including one who has a known CF-causing variant on the opposite chromosome. This CFTR variant has been reported in ClinVar (Variation ID: 500071), but is absent from a large population dataset. Functional studies demonstrate that this deep intronic variant creates a cryptic splice site that leads to aberrant splicing. We consider CFTR c.3874-4522A>G to be pathogenic.
Ambry Genetics	RCV000665784	SCV002622436	likely pathogenic	Cystic fibrosis	2022-09-13	criteria provided, single submitter	clinical testing	The c.3874-4522A>G intronic variant (also known as c.4005+5727A>G) results from an A to G substitution 4522 nucleotides before coding exon 24 in the CFTR gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in trans with a pathogenic CFTR mutation in an individual with classic cystic fibrosis (CF), and it has been observed in individuals with CFTR-related disorders, some of whom have other CFTR variants of undetermined phase (Bergougnoux A et al. J Cyst Fibros, 2019 07;18:468-475; Roth EK et al. PLoS One, 2011 Aug;6:e24445). One experimental study shows that this variant disrupts mRNA splicing; however, the variant's effect on splicing is incomplete (Bergougnoux A et al. J Cyst Fibros, 2019 07;18:468-475) This nucleotide position is not well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000665784	SCV003922695	pathogenic	Cystic fibrosis	2023-03-15	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3874-4522A>G is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3' acceptor site and one predicts the variant has no significant impact on splicing. At least one publication reports experimental evidence from sequencing RNA from compound heterozygous individuals with the variant, as well as a minigene assay, that shows this variant indeed affects mRNA splicing (Bergougnoux_2019). This study showed that the variant results in aberrant splicing which leads to the inclusion of a 125bp pseudo-exon, predicted to result in a premature stop codon, in 76% of RNA transcripts. The variant was absent in 31150 control chromosomes (gnomAD). c.3874-4522A>G has been reported in the literature in the compound heterozygous state in multiple individuals affected with Cystic Fibrosis and CFTR-related disorders, including cases where it has been confirmed to be in trans with a pathogenic variant (e.g. Roth_2011, Bergougnoux_2019 Morris-Rosendahl_2020). These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=4)/likely pathogenic (n=1) or VUS (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004530697	SCV004119590	likely pathogenic	CFTR-related disorder	2023-08-16	criteria provided, single submitter	clinical testing	The CFTR c.3874-4522A>G variant is predicted to interfere with splicing. This variant, previously reported as c.4005+5727A>G, has been reported in patients with cystic fibrosis (Bonini et al. 2015. PubMed ID: 25569440; Roth et al. 2011. PubMed ID: 21909392; Ellingford et al. 2022. PubMed ID: 35850704). This variant was also described in ten additional individuals with various CFTR-related phenotypes ranging from male infertility to cystic fibrosis with pancreatic insufficiency (Bergougnoux et al. 2018. PubMed ID: 30389601) and was reported in another study in the compound heterozygous state in twelve patients with cystic fibrosis (Morris-Rosendahl et al. 2020. PubMed ID: 32017858). In vitro splicing analysis indicates that this change results in inclusion of 125 bp (Bergougnoux et al. 2018. PubMed ID: 30389601). In Clinvar, this variant has been listed from 'uncertain' to 'pathogenic' by outside laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/500071/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, we classify this variant as likely pathogenic.
Baylor Genetics	RCV003471958	SCV004213281	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000597152	SCV004221694	pathogenic	not provided	2022-04-19	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000024 (1/41384 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported to co-occur with other pathogenic CFTR variants and has been associated with various phenotypes including male infertility and cystic fibrosis with pancreatic insufficiency (PMID: 30389601 (2019), 21909392 (2011), CFTR-France https://cftr.iurc.montp.inserm.fr/). In addition, a splicing analysis performed using cells taken from multiple individuals with cystic fibrosis has found that this variant results in aberrant splicing (PMID: 30389601 (2019)). Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000597152	SCV004562671	likely pathogenic	not provided	2023-10-06	criteria provided, single submitter	clinical testing	The CFTR c.3874-4522A>G variant (rs895394181) is reported in the literature in multiple individuals affected with cystic fibrosis and CFTR related disorders (Bergougnoux 2019, Roth 2011, Shen 2022, Su 2023). This variant is also reported in ClinVar (Variation ID: 500071) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. A minigene assay found this variant affects mRNA splicing resulting in the inclusion of a 125bp pseudo-exon that is predicted to result in a premature stop codon in a majority of RNA transcripts (Bergougnoux 2019). Based on available information, this variant is considered to be likely pathogenic. References: Bergougnoux A et al. Functional characterization and phenotypic spectrum of three recurrent disease-causing deep intronic variants of the CFTR gene. J Cyst Fibros. 2019 Jul;18(4):468-475. PMID: 30389601. Roth EK et al. The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients. PLoS One. 2011;6(8):e24445. PMID: 21909392. Shen Y et al. Genetic spectrum of Chinese children with cystic fibrosis: comprehensive data analysis from the main referral centre in China. J Med Genet. 2022 Jul 20;60(3):310–5. PMID: 35858753. Su Y et al. Case report of a pediatric Chinese cystic fibrosis patient with the c.1521_1523delCTT/c.3874-4522A>G genotype. Pediatr Pulmonol. 2023 Feb;58(2):556-558. PMID: 36349818.