ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3468+2dup (rs1554392800)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000576486 SCV000677602 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726994 SCV000704794 likely pathogenic not provided 2016-12-27 criteria provided, single submitter clinical testing
Mendelics RCV000576486 SCV000886225 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001132 SCV001158274 pathogenic not specified 2019-03-05 criteria provided, single submitter clinical testing The CFTR c.3468+2dupT variant, also known as c.3468+2_3468+3insT, is published in several individuals with pancreatic insufficient CF (Krenkova 2013, Soltysova 2018, Zietkiewicz 2014). The variant is reported in the ClinVar database (Variation ID: 487380), but is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a highly conserved region, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Considering available information, this variant is classified as pathogenic. References: Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. Soltysova A et al. Comprehensive genetic study of cystic fibrosis in Slovak patients in 25 years of genetic diagnostics. Clin Respir J. 2018 Mar;12(3):1197-1206. Zietkiewicz E et al. CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients. PLoS One. 2014 Feb 26;9(2):e89094.
Integrated Genetics/Laboratory Corporation of America RCV000576486 SCV001362680 pathogenic Cystic fibrosis 2019-03-08 criteria provided, single submitter clinical testing Variant summary: CFTR c.3468+2dupT (also called or c.3468+2_3468+3insT or 3600+2insT according to an older nomenclature) alters a 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: 5/5 predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 276292 control chromosomes (gnomAD). c.3468+2dupT has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Van Biervliet 2007, Krenkova 2012, Zietkiewicz 2014). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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