Submissions for variant NM_000492.4(CFTR):c.4243-16A>G

dbSNP: rs780125251

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	RCV000780110	SCV000917154	uncertain significance	not specified	2021-12-27	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.4243-16A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 249724 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00012 vs 0.013), allowing no conclusion about variant significance. c.4243-16A>G has been reported in the literature in one individual with elevated sweat chloride levels (Mazumdar_2015). Thid report does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. 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 uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002536862	SCV003027411	likely benign	Cystic fibrosis	2023-11-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002536862	SCV003855877	benign	Cystic fibrosis	2022-11-10	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003736905	SCV004565240	uncertain significance	not provided	2023-07-27	criteria provided, single submitter	clinical testing	The CFTR c.4243-16A>G variant (rs780125251) is reported in the CFTR France database in an individual with pancreatitis and an individual with CBAVD (see link). This variant is also reported in ClinVar (Variation ID: 632746). It is found in the general population with an overall allele frequency of 0.01% (31/249724 alleles) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. Due to limited information, the clinical significance of this variant is uncertain at this time. References: CFTR France database link: https://cftr.iurc.montp.inserm.fr/cgi-bin/affiche.cgi?variant=c.4243-16A%3EG&provenance=0
PreventionGenetics, part of Exact Sciences	RCV004540097	SCV004790119	likely benign	CFTR-related disorder	2022-12-09	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).