Submissions for variant NM_000492.4(CFTR):c.1585-9412A>G

gnomAD frequency: 0.00001  dbSNP: rs397508229

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000577289	SCV000795846	uncertain significance	Cystic fibrosis	2017-11-20	criteria provided, single submitter	clinical testing
CFTR-France	RCV000577289	SCV001169471	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000577289	SCV002705653	pathogenic	Cystic fibrosis	2018-10-26	criteria provided, single submitter	clinical testing	The c.1585-9412A>G intronic pathogenic mutation results from an A to G substitution 9412 nucleotides upstream from coding exon 12 in the CFTR gene. This mutation (reported as c.1584+18672A>G) has been detected in multiple individuals affected with cystic fibrosis who have a pathogenic mutation on the other chromosome (Costantino L et al. Am. J. Respir. Cell Mol. Biol., 2013 May;48:619-25). In addition, this mutation has been shown to activate two out-of-frame pseudoexons (104 and 65 base pairs) by creating a splice donor site (Costantino L et al. J. Cyst. Fibros., 2010 Dec;9:411-8; Costantino L et al. Am. J. Respir. Cell Mol. Biol., 2013 May;48:619-25; Felício V et al. Clin. Genet., 2017 03;91:476-481). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577289	SCV003275197	pathogenic	Cystic fibrosis	2024-12-08	criteria provided, single submitter	clinical testing	This sequence change falls in intron 11 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 individuals with cystic fibrosis (PMID: 20875776, 23349053). ClinVar contains an entry for this variant (Variation ID: 53284). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000577289	SCV003927243	likely pathogenic	Cystic fibrosis	2023-03-10	criteria provided, single submitter	clinical testing	This intronic CFTR variant has been identified in multiple individuals with features of cystic fibrosis who carry a second CF-causing variant. This variant (rs397508229) is rare (<0.1%) in a large population dataset (gnomAD: 1/152080 total alleles; 0.0006575%; no homozygotes) and has been reported in ClinVar (Variation ID: 53284). Functional studies demonstrate that this deep intronic variant creates a cryptic splice donor site that leads to aberrant splicing. We consider CFTR c.1585-9412A>G to be likely pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577289	SCV000679111	not provided	Cystic fibrosis		no assertion provided	literature only