Submissions for variant NM_000492.4(CFTR):c.3717+5G>A

dbSNP: rs193922520

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000029530	SCV000924226	pathogenic	Cystic fibrosis	2017-12-08	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029530	SCV000052182	pathogenic	Cystic fibrosis	2022-10-26	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3717+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing as resulting in a shortened transcript, although the primary data are not provided (example, Joynt_2020). The variant allele was found at a frequency of 4.1e-06 in 246164 control chromosomes. c.3717+5G>A has been reported in the literature as a homozygous genotype in at-least one individual and with limited genotype information in multiple individuals affected with Cystic Fibrosis (e.g. Bonyadi_2017, Bustami_2018, Kilinc_2002. These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory and an expert panel (CFTR-2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001004503	SCV001163548	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000029530	SCV002574083	likely pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient 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: PM2_SUP, PM3_STR, PP3, PP4
Ambry Genetics	RCV000029530	SCV002623116	uncertain significance	Cystic fibrosis	2022-09-02	criteria provided, single submitter	clinical testing	The c.3717+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 22 in the CFTR gene. This variant was detected as homozygous in an individual with classic cystic fibrosis (Kilin&ccedil; MO et al. Am J Med Genet, 2002 Dec;113:250-7). In addition, this variant has <10% of wild type quantity in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 09/01/2022). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002496446	SCV002810315	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-03-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029530	SCV003242066	likely pathogenic	Cystic fibrosis	2022-05-27	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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: 35875). This variant is also known as 3849+5G>A. This variant has been observed in individual(s) with cystic fibrosis (PMID: 12439892, 23974870). This variant is present in population databases (rs193922520, gnomAD 0.003%). This sequence change falls in intron 22 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. It affects a nucleotide within the consensus splice site.
PreventionGenetics, part of Exact Sciences	RCV004724756	SCV005338903	pathogenic	CFTR-related disorder	2024-09-25	no assertion criteria provided	clinical testing	The CFTR c.3717+5G>A variant is predicted to interfere with splicing. This variant, also known as c.3849+5G>A, has been reported in multiple individuals with cystic fibrosis and pancreatic insufficiency (http://www.cftr2.org; Kilinc et al. 2002. PubMed ID: 12439892). It has also been reported in an individual with unilateral congenital absence of the vas deferens (Akinsal et al. 2018. PubMed ID: 29484681) and reported as a lower risk variant for patients with cystic fibrosis to develop cystic fibrosis-related diabetes (CFRD) (Adler et al. 2008 PMID:18535191). Of note, another variant impacting the same splice site (c.3717+5G>T) has been reported together with delta508 in a patient with severe presentation (Aalbers et al. 2022. PubMed ID: 35110005). Functional assays in patient-derived intestinal organoids showed minimum swelling supporting loss of function (Aalbers et al. 2022. PubMed ID: 35110005). The c.3717+5G>A variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jarganathan et al. 2019. PubMed ID: 30661751) and has been confirmed to cause abnormal splicing, resulting in a truncated protein (Joynt et al. 2020. PMID: 33085659). It is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is interpreted as pathogenic by the CFTR2 expert group in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/35875/). This variant is interpreted as pathogenic.