Submissions for variant NM_000492.4(CFTR):c.3717+1G>A

dbSNP: rs750558115

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780151	SCV000917198	pathogenic	not specified	2018-04-16	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3717+1G>A 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 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.3e-06 in 241448 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (8.3e-06 vs 1.30e-02), allowing no conclusion about variant significance. c.3717+1G>A has been reported in the literature in individuals affected with Cystic Fibrosis (Greil_1993, Keyeux_2003, Nahida_2011, Alonso_2007). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
CFTR-France	RCV001009420	SCV001169358	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV001009420	SCV002574082	likely pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_STR, PM2_SUP, PM3
Labcorp Genetics (formerly Invitae), Labcorp	RCV001009420	SCV003440164	pathogenic	Cystic fibrosis	2022-04-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 22 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 (rs750558115, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 7509231, 12938099, 17331079, 21449922). 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 3849+1G>A. ClinVar contains an entry for this variant (Variation ID: 632759). 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.
Natera, Inc.	RCV001830671	SCV002075870	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing