Submissions for variant NM_000492.4(CFTR):c.489+2T>C

dbSNP: rs397508732

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000577437	SCV000790974	likely pathogenic	Cystic fibrosis	2017-04-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577437	SCV000919189	likely pathogenic	Cystic fibrosis	2021-07-07	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.489+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. One predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245226 control chromosomes. c.489+2T>C has been reported in the primary literature as a homozygous genotype in at-least one individual affected with Cystic Fibrosis (example, Malone_1998) and has been subsequently cited by others (example, Bobadilla_2002, Kabra_2007, Wachter_2017). Additionally, at-least one patient who was reportedly compound heterozygous with the p.F508del variant on the other allele has been reported as an unpublished personal correspondence in the Sick kids database. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories and the CFTR-France database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, pending the identification of additional well phenotyped and extensively genotyped CF patients with this variant and/or a study describing an unequivocal functional outcome, this splice site variant was classified as likely pathogenic.
CFTR-France	RCV000577437	SCV001169314	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Invitae	RCV000577437	SCV001587013	pathogenic	Cystic fibrosis	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 9482579, 15371902, 23974870). This variant is also known as 621+2T>C. ClinVar contains an entry for this variant (Variation ID: 53969). 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.
Baylor Genetics	RCV003474604	SCV004213443	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-08-01	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577437	SCV000679160	not provided	Cystic fibrosis		no assertion provided	literature only