Submissions for variant NM_000492.4(CFTR):c.3468+6T>C

gnomAD frequency: 0.00001  dbSNP: rs547442588

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000664596	SCV000788586	uncertain significance	Cystic fibrosis	2016-12-28	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000664596	SCV001164323	uncertain significance	Cystic fibrosis	2020-02-19	criteria provided, single submitter	clinical testing	A heterozygous splice site variation in intron 21 of the CFTR gene was detected. The observed variant c.3468+6T>C has been reported in ClinVar as variant of uncertain significance previously. The variant is found to have allele frequency of <0.1% in the gnomAD database. In summary, the variant meets our criteria to be classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192463	SCV001360600	uncertain significance	not specified	2024-06-25	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3468+6T>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. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 250594 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (4.8e-05 vs 0.013), allowing no conclusion about variant significance. c.3468+6T>C has been reported in the literature in an individual affected with Cystic Fibrosis (examples: Ashavaid_2012, Deepak_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. 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: 23405520, 27625827). ClinVar contains an entry for this variant (Variation ID: 549991). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000664596	SCV002027504	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000664596	SCV002618776	uncertain significance	Cystic fibrosis	2024-07-10	criteria provided, single submitter	clinical testing	The c.3468+6T>C intronic variant results from a T to C substitution 6 nucleotides after coding exon 21 in the CFTR gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This nucleotide position is conserved on limited sequence alignment. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this donor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear
Fulgent Genetics, Fulgent Genetics	RCV002485518	SCV002791011	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-02-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000664596	SCV003001824	uncertain significance	Cystic fibrosis	2024-05-08	criteria provided, single submitter	clinical testing	This sequence change falls in intron 21 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. This variant is present in population databases (rs547442588, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with Cystic Fibrosis (PMID: 27625827, 28440306). This variant is also known as c.3600+6(T‚ÜíC). ClinVar contains an entry for this variant (Variation ID: 549991). 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 is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc.	RCV001835066	SCV002075830	uncertain significance	CFTR-related disorder	2017-05-09	no assertion criteria provided	clinical testing