Submissions for variant NM_000492.3(CFTR):c.273+3A>C (rs74467662)

Total submissions: 4

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	likely pathogenic	Cystic fibrosis	2019-06-28	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. 2/4 computational tools predict the variant weakens/abolishes a 5' splicing donor site. In support of the predicted effect on splicing, Macek et al points 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 and Macek_1997). In the literature, the variant has been reported in several African American patients affected with Cystic Fibrosis (CF) (e.g. Macek_1997, Watson_2004). 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). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other submitters, including an expert panel (CFTR2), have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001004421	SCV001163465	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Myriad Women's Health, 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.