Submissions for variant NM_000492.4(CFTR):c.274-1G>C

dbSNP: rs121908792

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000664921	SCV000788954	likely pathogenic	Cystic fibrosis	2016-12-22	criteria provided, single submitter	clinical testing
CFTR-France	RCV000664921	SCV001169508	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Neuberg Centre For Genomic Medicine, NCGM	RCV000664921	SCV002073087	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing	The splice acceptor variant c.274-1G>C in CFTR (NM_000492.4) has been previously reported in an affected patient (Claustres M et al). The variant has been submitted to ClinVar as Pathogenic. The c.274-1G>C variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant affects an invariant splice nucleotide and hence is predicted to cause loss of function. For these reasons, this variant has been classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000664921	SCV002245860	pathogenic	Cystic fibrosis	2023-02-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 53554). This variant is also known as 406-1G>C. Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 1284541, 15365999). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 3 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000664921	SCV002600702	likely pathogenic	Cystic fibrosis	2022-10-24	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.274-1G>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: Four predict the variant abolishes a canonical 3' acceptor site. Three predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250598 control chromosomes. c.274-1G>C has been reported in the literature in at leat one individual affected with Cystic Fibrosis (Bonizzato_1992, Lucarelli_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV004566874	SCV005057479	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-11-13	criteria provided, single submitter	clinical testing