Submissions for variant NM_000492.4(CFTR):c.490-1G>A

gnomAD frequency: 0.00002  dbSNP: rs397508734

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672764	SCV000797902	likely pathogenic	Cystic fibrosis	2018-02-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004433	SCV001163478	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000672764	SCV001425431	pathogenic	Cystic fibrosis	2020-02-19	criteria provided, single submitter	clinical testing	This variant has been previously identified in patients with cystic fibrosis and is classified as likely pathogenic by one ClinVar submitter. It (rs397508734) is rare (<0.1%) in a large population dataset ( gnomAD: 4/249200 total alleles; 0.002%; no homozygotes). Bioinformatic analysis predicts that this canonical splice site variant would affect normal exon 4 splicing, although this has not been confirmed experimentally to our knowledge. We consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672764	SCV001589435	pathogenic	Cystic fibrosis	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs397508734, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 23857699, 26160248). This variant is also known as c.622-1G>A. ClinVar contains an entry for this variant (Variation ID: 53974). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000672764	SCV002639617	likely pathogenic	Cystic fibrosis	2022-09-12	criteria provided, single submitter	clinical testing	The c.490-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 5 of the CFTR gene. This alteration was reported as compound heterozygous in two individuals with cystic fibrosis (CF) and pancreatic insufficiency (PI), moderate pulmonary disease, and elevated sweat chloride levels (Zielenski J et. al. Cystic Fibrosis Mutation Database [database online] Toronto, ON, Canada: SickKids;1995). Additionally, this alteration was detected as compound heterozygous in an individual with CF, who had mild pulmonary disease and elevated sweat chloride levels (Krzyanowska P et al. Sci Rep, 2015 Jul;5:12000). This nucleotide position is highly conserved on sequence alignment. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672764	SCV004038902	likely pathogenic	Cystic fibrosis	2024-10-11	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.490-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of CFTR function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. Two predict the variant creates a 3' acceptor site. One predicts the variant strengthens a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 249200 control chromosomes. c.490-1G>A has been reported in the literature in individuals affected with Cystic Fibrosis who were reported as presumed compound heterozygous with other pathogenic variants (Krzyzanowska_2015, Montgomery_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26160248, 29884450). ClinVar contains an entry for this variant (Variation ID: 53974). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV004566885	SCV005057444	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831793	SCV002080151	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing