ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3717+40A>G (rs397508595)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000576505 SCV000677605 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Ambry Genetics RCV000623465 SCV000742529 pathogenic Inborn genetic diseases 2017-07-05 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727551 SCV000854777 likely pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
CFTR-France RCV001009536 SCV001169631 pathogenic Cystic fibrosis; CFTR-related disorders 2018-03-26 criteria provided, single submitter curation the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285627 SCV001472091 pathogenic none provided 2020-08-10 criteria provided, single submitter clinical testing The CFTR c.3717+40A>G variant (rs397508595) is reported in the literature in multiple individuals affected with cystic fibrosis and one individual with congenital bilateral absence of the vas deferens (Lee 2017, Steiner 2011, CFTR2 database). In addition, this variant has been observed in testing performed at ARUP Laboratories in an individual with elevated sweat chloride and a second pathogenic variant. The c.3717+40A>G variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site. Indeed, functional studies of this variant demonstrate it leads to the inclusion of 40 additional nucleotides, causing a frameshift and decreased mRNA levels (Lee 2017). Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org/ Lee M et al. Systematic Computational Identification of Variants That Activate Exonic and Intronic Cryptic Splice Sites. Am J Hum Genet. 2017;100(5):751-765. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011;32(8):912-920.
Baylor Genetics RCV000576505 SCV001527342 pathogenic Cystic fibrosis 2018-08-23 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV000576505 SCV001591261 pathogenic Cystic fibrosis 2020-10-26 criteria provided, single submitter clinical testing This sequence change falls in intron 22 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another CFTR variant in individuals affected with cystic fibrosis or congenital absence of the vas deferens (PMID: 28475858, 28475858, 23974870). This variant is also known as 3849+40A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 53789). Studies have shown that this variant is associated with activation of a cryptic donor 40 nucleotides downstream of the exon 22 canonical donor , which introduces a frameshift (PMID:28475858). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000576505 SCV000794669 likely pathogenic Cystic fibrosis 2017-10-11 no assertion criteria provided clinical testing

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