Submissions for variant NM_000492.4(CFTR):c.4243-20A>G

gnomAD frequency: 0.00086  dbSNP: rs138025486

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586481	SCV000601119	uncertain significance	not provided	2019-02-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778983	SCV000697017	likely benign	not specified	2024-07-25	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.4243-20A>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing, which has been confirmed by minigene assay (Leman_2020). The variant allele was found at a frequency of 0.00021 in 249550 control chromosomes, predominantly at a frequency of 0.0027 within the African or African-American subpopulation in the gnomAD database. This frequency is lower than the maximum expected for a pathogenic variant in CFTR causing Cystic Fibrosis (CF) (0.013), however, prevalence of CF is known to be lower in Africans (e.g. PMID 9506637), therefore this variant may still represent a benign polymorphism. c.4243-20A>G has been reported in the literature in a compound heterozygous individual affected with CF who carried two additional variants (F508del and c.3165dupA; phase not specified) (Raraigh_2022), providing additional evidence for a benign role. c.4243-20A>G has also been reported in heterozygosity in individuals affected with various conditions, including chronic- or recurrent pancreatitis, Pseudomonas pneumonia, idiopathic bronchiectasis and asthma (Keiles_2006, Fajac_2008, Crespo-Lessmann_2021). The variant was also identified in individuals with a positive newborn screen result (Ridge_2013, Lefterova_2016, Salinas_2017, Kasi_2020), however, one of these individuals also carried an additional variant (F508del; phase not specified) and was reportedly asymptomatic with a normal sweat chloride level (Kasi_2020), whereas the other individual carried two other variants c.2988+1G>A, c.224G>T (p.Arg75Leu) (classified internally as pathogenic for CF, and VUS-possibly pathogenic for CBAVD, respectively), which could potentially explain the positive newborn screen finding (Ridge_2013). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. In addition, this variant was also present in one internal sample, together with 5T_TG11 (internally classified as pathogenic for CBAVD) and c.224G>T (p.Arg75Leu), indicating the variant of interest may be a benign variant. The following publications have been ascertained in the context of this evaluation (PMID: 17003641, 18507830, 23343000, 26847993, 28465863, 31844968, 31992191, 34086689, 33946859, 34782259, 36409994). ClinVar contains an entry for this variant (Variation ID: 439084). Based on the evidence outlined above, the variant was classified as likely benign.
Eurofins Ntd Llc (ga)	RCV000586481	SCV000703817	uncertain significance	not provided	2018-06-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000664604	SCV000788597	likely benign	Cystic fibrosis	2017-01-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000664604	SCV001000837	likely benign	Cystic fibrosis	2024-01-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586481	SCV001159192	likely benign	not provided	2023-05-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002255421	SCV002529727	likely benign	Hereditary pancreatitis	2020-11-25	criteria provided, single submitter	curation
Ambry Genetics	RCV000664604	SCV002628648	likely benign	Cystic fibrosis	2023-04-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
PreventionGenetics, part of Exact Sciences	RCV004541576	SCV004767334	likely benign	CFTR-related disorder	2022-10-14	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).