Submissions for variant NM_000492.4(CFTR):c.1393-1G>A

dbSNP: rs397508200

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056347	SCV000071451	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000056347	SCV000205857	pathogenic	Cystic fibrosis	2013-10-18	criteria provided, single submitter	clinical testing	The 1393-1G>A variant in CFTR causes cystic fibrosis when combined with another CF-causing variant. It has been previously identified in 2 homozygous and 3 comp ound heterozygous individuals with cystic fibrosis and was found to segregate wi th disease in 1 family member (Dork 1993, Ramalho 2003, Wahab 2004, Ashavaid 200 5, Nikolic 2013). It has not been identified in large population studies. This v ariant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent pro tein (Ramalho 2003). In summary, this variant meets our criteria to be classifie d as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies, absence from controls, and functional evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506225	SCV000601043	pathogenic	not provided	2017-04-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506518	SCV000603063	pathogenic	not specified	2017-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056347	SCV000696839	pathogenic	Cystic fibrosis	2017-03-30	criteria provided, single submitter	clinical testing	Variant summary: The c.1393-1G>A in CFTR gene is a splice-site variant that alters a highly conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical splicing acceptor sequence, although these predictions are yet to be confirmed by the functional studies. The variant is present in control dataset of ExAC at a low frequency of 0.000049 (6/121108 chrs tested) which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.0129). This variant appears to be very common in Palestina (Siryani, 2015). The variant was found homozygously or in compound heterozygosity in multiple affected individuals with established dx of CF. Patients, homozygous for the variant of interest, presented with elevated sweat Cl- (ranging from 110 to 148 mmol/L) and PI. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.
Baylor Genetics	RCV001004449	SCV001163494	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056347	SCV001169562	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Invitae	RCV000056347	SCV001579489	pathogenic	Cystic fibrosis	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 10 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 (rs397508200, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with cystic fibrosis and congenital bilateral absence of the vas deferens (PMID: 7682196, 9239681, 9482579, 15727251, 17662673, 18373402, 18782298, 21198395, 21909392, 23933162, 25688174, 26208274, 26708955). This variant is also known as c.1525-1G>A. ClinVar contains an entry for this variant (Variation ID: 53242). 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.
Arcensus	RCV000056347	SCV002564583	pathogenic	Cystic fibrosis	2013-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000056347	SCV002696017	pathogenic	Cystic fibrosis	2022-08-17	criteria provided, single submitter	clinical testing	The c.1393-1G>A intronic pathogenic mutation (also known as 1525-1G>A) results from a G to A substitution one nucleotide upstream from coding exon 11 of the CFTR gene. This mutation was first reported in an Afghani individual with elevated sweat chloride levels and clinical features of cystic fibrosis (CF); however, a second CFTR alteration was not identified (Dörk T et al. Genomics, 1993 Mar;15:688-91). A Serbian individual homozygous for this mutation presented with liver steatosis at age 7 years and later developed respiratory symptoms; he had mild pancreatic insufficiency and elevated sweat chloride levels (Nikolic A et al. J. Cyst. Fibros., 2014 Jan;13:111-3). Splicing analysis in colonic biopsies from two related Pakistani individuals with CF with c.1393-1G>A and p.F508del demonstrated exon skipping or the use of alternative splice sites due to the intronic alteration. Furthermore, the same study demonstrated that CFTR mediated chloride secretion was absent in the colonic biopsies of the affected individuals (Ramalho AS et al. J. Med. Genet., 2003 Jul;40:e88). 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 a disease-causing mutation.
Baylor Genetics	RCV003473452	SCV004213368	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905002	SCV004718913	pathogenic	CFTR-related condition	2023-12-30	criteria provided, single submitter	clinical testing	The CFTR c.1393-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant, previously described as c.1525-1G>A using legacy nomenclature, has been reported to be causative for cystic fibrosis (Castellani et al. 2008. PubMed ID: 18456578; Supplemental table 2, Sosnay et al. 2013. PubMed ID: 23974870). The c.1393-1G>A variant has also been reported in patient with idiopathic chronic pancreatitis who had a corresponding pathogenic variant in the SPINK1 gene (Supplemental table 1, Midha et al. 2010. PubMed ID: 20551465). This variant is reported in 0.026% of alleles in individuals of South Asian descent in gnomAD. Variants that disrupt the consensus splice acceptor site in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.
Natera, Inc.	RCV001831726	SCV002080586	pathogenic	CFTR-related disorders	2017-03-17	no assertion criteria provided	clinical testing