Submissions for variant NM_000492.4(CFTR):c.274-2A>G

dbSNP: rs397508426

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000577517	SCV000924241	pathogenic	Cystic fibrosis	2017-12-08	reviewed by expert panel	research
Counsyl	RCV000577517	SCV000799014	pathogenic	Cystic fibrosis	2018-04-04	criteria provided, single submitter	clinical testing
CFTR-France	RCV000577517	SCV001169510	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577517	SCV001361715	pathogenic	Cystic fibrosis	2024-08-12	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.274-2A>G 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: Five predict the variant abolishes a 3 acceptor site. Two predict the variant creates a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250598 control chromosomes. c.274-2A>G has been reported in the literature and in our internal database in multiple homozygous individuals affected with Cystic Fibrosis (el-Harith 1997, Panickar 2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 53556). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577517	SCV001590841	pathogenic	Cystic fibrosis	2024-09-13	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 9429141). This variant is also known as 406-2A>G. ClinVar contains an entry for this variant (Variation ID: 53556). 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.
3billion, Medical Genetics	RCV000577517	SCV003841753	pathogenic	Cystic fibrosis	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000053556). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV003474551	SCV004213527	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-04-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000577517	SCV005107522	likely pathogenic	Cystic fibrosis	2024-05-28	criteria provided, single submitter	clinical testing	The c.274-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 4 in the CFTR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). Designated 406-2 A to G, this variant was detected as homozygous in a 20-month-old child with CF diagnosed at birth due to meconium ileus and since diagnosed with pancreatic insufficiency and failure to thrive (el-Harith EA et al. J Med Genet, 1997 Dec;34:996-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577517	SCV000679017	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV001831755	SCV002080109	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing