ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.579+3A>G (rs397508761)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000056396 SCV000071574 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Invitae RCV000056396 SCV000075216 pathogenic Cystic fibrosis 2019-09-17 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs397508761, ExAC 0.003%). This variant has been reported in many individuals affected with cystic fibrosis, often with a second pathogenic variant in trans with this allele (PMID: 7524913, 23974870, 21097845). Generally individuals with this variant were pancreatic-sufficient (PMID: 18456578). This variant is also known as c.711+3A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 54010). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant leads to skipping of exon 5 in vitro and in vivo (PMID: 23974870, 21097845). A version of the CFTR protein lacking exon 5 is improperly processed and lacks full channel activity (PMID: 8968585). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506239 SCV000601126 pathogenic not provided 2017-04-14 criteria provided, single submitter clinical testing
Mendelics RCV000056396 SCV000886250 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001964 SCV001159764 pathogenic not specified 2019-05-20 criteria provided, single submitter clinical testing The c.579+3A>G variant (rs397508761), also known as 711+3A>G, has been reported in individuals diagnosed with cystic fibrosis, and often associated with pancreatic sufficiency (Sheridan 2011, CFTR2 database). It is reported as pathogenic in ClinVar (Variation ID: 54010) and observed at a low overall frequency of 0.002% (5/275858 alleles) in the Genome Aggregation Database. This is an intronic variant at a nucleotide that is moderately conserved, and computational algorithms (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Functional characterization indicates that the variant causes the skipping of exon 5, leading to the absence of correctly spliced mRNA (Sheridan 2011, Raynal 2013, Sosnay 2013). Based on available information, this variant is considered pathogenic. References: Link to CFTR2 database: http://cftr2.org/ Raynal C et al. (2013) A classification model relative to splicing for variants of unknown clinical significance: application to the CFTR gene. Hum Mutat. 34(5):774-84. Sheridan M et al. (2011) CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR. J Med Genet. 48(4):235-41. Sosnay PR et al. (2013) Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 45(10):1160-7.
Baylor Genetics RCV001004438 SCV001163483 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009385 SCV001169238 pathogenic Cystic fibrosis; CFTR-related disorders 2018-01-29 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Integrated Genetics/Laboratory Corporation of America RCV000056396 SCV001361718 pathogenic Cystic fibrosis 2019-10-07 criteria provided, single submitter clinical testing Variant summary: CFTR c.579+3A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict that the variant abolishes a 5' splicing donor site. In addition, several publications report experimental evidence that this variant affects mRNA splicing (e.g. Sheridan_2011, Raynal_2013, Sosnay_2013). The variant allele was found at a frequency of 1.6e-05 in 249988 control chromosomes (gnomAD). c.579+3A>G has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Hughes_1996, Petereska_1998, Gilljam_2004, Krasnov_2008, Sheridan_2011, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics,Johns Hopkins University RCV000056396 SCV001425308 pathogenic Cystic fibrosis 2020-03-09 criteria provided, single submitter clinical testing Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

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