Submissions for variant NM_000492.4(CFTR):c.273+3A>C

dbSNP: rs74467662

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000029501	SCV000245989	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029501	SCV000052152	pathogenic	Cystic fibrosis	2023-06-19	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.273+3A>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Two computational tools predict the variant weakens a canonical 5' donor site and one predicts it abolishes the site. In support of the predicted effect on splicing, Macek et al. point out that cytosine is the least common nucleotide at the +3 position of splice-donor sites, and that mutations at this location have been reported to cause aberrant RNA splicing (Macek_1997). However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250744 control chromosomes (gnomAD). c.273+3A>C has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Macek_1997, Watson_2004, Dork_1998, Raraigh_2022, Bresnick_2021), and at least one family was reported as compound heterozygous with another pathogenic variant. In addition, the CFTR2 database reports 10 patients with this variant, stating that this variant causes CF when combined with another CF-causing variant (average sweat chloride levels in patients harboring this variant was found to be 109 mEq/L and 100% of these patients were pancreatic insufficient). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15371902, 15025720, 16049310, 9950364, 12089190, 20616359, 9150159, 21796730, 16244288, 11471192, 22975760, 26708955, 9683582, 34782259, 34857524). Four submitters, including an expert panel (CFTR2), have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001004421	SCV001163465	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000029501	SCV001193953	likely pathogenic	Cystic fibrosis	2019-12-04	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.273+3A>C(aka 405+3A>C) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 9150159 and 11388756. Classification of NM_000492.3(CFTR):c.273+3A>C(aka 405+3A>C) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029501	SCV002288892	likely pathogenic	Cystic fibrosis	2023-08-04	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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: 35846). This variant is also known as 405+3A>C. This variant has been observed in individuals with cystic fibrosis (PMID: 23974870). This sequence change falls in intron 3 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.
Ambry Genetics	RCV000029501	SCV002743647	likely pathogenic	Cystic fibrosis	2020-01-10	criteria provided, single submitter	clinical testing	The c.273+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 3 in the CFTR gene. In one study, this variant was identified in two African American individuals with cystic fibrosis (CF) and it has been described as a common African American CF mutation (Macek M et al. Am. J. Hum. Genet., 1997 May;60:1122-7). In our internal cohort, this variant was identified with a known CF mutation in multiple diagnostic cases in our laboratory; however, the phase is not known (Ambry internal data). This nucleotide position is conserved in available vertebrate species. This variant was not reported in the gnomAD database, with coverage at this position. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics	RCV003473133	SCV004213514	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-05-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003482230	SCV004228234	pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	PP3, PM2, PM3_very_strong