ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.165-3C>T (rs200337193)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000046385 SCV000924237 pathogenic Cystic fibrosis 2017-12-08 reviewed by expert panel research
Counsyl RCV000046385 SCV000220698 likely pathogenic Cystic fibrosis 2014-09-17 criteria provided, single submitter literature only
Baylor Genetics RCV001004227 SCV001163103 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009538 SCV001169633 pathogenic Cystic fibrosis; CFTR-related disorders 2015-07-01 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
Ambry Genetics RCV001012598 SCV001173070 likely pathogenic Inborn genetic diseases 2018-10-30 criteria provided, single submitter clinical testing The c.165-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 3 in the CFTR gene. This variant was detected in conjunction with a second CFTR alteration in a 44-year-old woman with cystic fibrosis who presented with elevated sweat chloride levels, pulmonary symptoms, and pancreatic sufficiency; however, the pathogenicity of the second alteration was uncertain (Bienvenu T et al. Hum. Genet., 1994 Jul;94:65-8). This alteration was also reported in a fetus with meconium ileus who had p.F508del (Oca F et al. Clin. Chem., 2009 Dec;55:2214-7). In addition, another variant at the same nucleotide position (c.165-3C>A) has been reported in an individual with pulmonary disease, pancreatic insufficiency, and high sweat chloride level; this individual carried p.F508del on the other chromosome (Strandvik B et al. Genet. Test., 2001;5:235-42). In vitro analysis of c.165-3C>T showed abnormal RNA splicing and protein expression (Bienvenu T et al. Hum. Genet., 1994 Jul;94:65-8; The Clinical and Functional TRanslation of CFTR (CFTR2), available at http://cftr2.org, accessed <April 11, 2018>). This nucleotide position is highly conserved in available vertebrate species. This alteration is predicted by ESEfinder to weaken the efficacy of the native acceptor splice site. Using the Human Splicing Finder (HSF) splice site prediction tool, this alteration is also predicted to weaken the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000046385 SCV001338125 likely pathogenic Cystic fibrosis 2020-01-31 criteria provided, single submitter clinical testing Variant summary: CFTR c.165-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/4 computational tools predict the variant slightly weakens a canonical 3 acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in the skipping of exon 3 (Bienvenu_1994). The variant allele was found at a frequency of 2.4e-05 in 250574 control chromosomes (gnomAD). c.165-3C>T has been reported in the literature in individuals affected with Cystic Fibrosis (Bienvenu_1994, Hubert_1996, Claustres_2000). These data indicate that the variant is likely to be associated with disease. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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