ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1731C>T (p.Tyr577=) (rs55928397)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420715 SCV000052138 uncertain significance not specified 2021-05-17 criteria provided, single submitter clinical testing Variant summary: CFTR c.1731C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. Multiple functional studies showed that this variant has an effect on splicing, with as little as approximately 5% exon 13 inclusion (legacy name exon 12), however this effect is dependent on other neighboring variants (Raponi_2006, Pagani_2003, Amaral_2004, FernandezAlanis_2012). At-least one recent functional study reports no significant effect of this variant on splicing (Ramalho_2015). To our knowledge no studies reporting a functional impact of this variant on CFTR channel activity have been reported. The variant allele was found at a frequency of 0.00021 in 250348 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00021 vs 0.013), allowing no conclusion about variant significance. c.1731C>T has been reported in the literature in individuals affected with idiopathic chronic pancreatitis (example, Audrezet_2008, Nakano_2015). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV001012890 SCV001173404 uncertain significance Inborn genetic diseases 2019-11-29 criteria provided, single submitter clinical testing The c.1731C>T variant (also known as p.Y577Y), located in coding exon 13, results from a C to T substitution at nucleotide position 1731 of the CFTR gene. This nucleotide substitution does not change the amino acid at codon 577. Functional splicing assays have observed this variant to cause exon 12 skipping (exon 13 based on current exon numbering) using in vitro hybrid minigene transcripts, and authors suggested it may affect exonic splicing regulatory elements (Pagani F et al. Hum. Mol. Genet., 2003 May;12:1111-20; Fernandez Alanis E et al. Hum. Mol. Genet., 2012 Jun;21:2389-98). This nucleotide position is poorly conserved in available vertebrate species. Based on available evidence to date, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289824 SCV001477819 uncertain significance none provided 2020-02-04 criteria provided, single submitter clinical testing The CFTR c.1731C>T; p.Tyr577Tyr variant (rs55928397), is reported in the literature in an individual affected with cystic fibrosis (SickKids CFTR database). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (46/128572 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 35832). This is a synonymous variant in a weakly conserved nucleotide; however, it occurs in an exonic splicing enhancer element and minigene assays indicate it may lead to increased skipping of exon 12 (Amaral 2004, Fernandez Alanis 2012, Pagani 2005), although this has not been demonstrated in patient cells with this variant. Given the lack of clinical and functional data, the significance of the c.1731C>T variant is uncertain at this time. References: SickKids CFTR database entry for p.Tyr577Tyr: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=755 Amaral MD et al. Quantitative methods for the analysis of CFTR transcripts/splicing variants. J Cyst Fibros. 2004 Aug;3 Suppl 2:17-23. Fernandez Alanis et al. An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. Hum Mol Genet. 2012 Jun 1;21(11):2389-98. Pagani F et al. Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution. Proc Natl Acad Sci U S A. 2005 May 3;102(18):6368-72.
Invitae RCV000029487 SCV001620988 likely benign Cystic fibrosis 2020-10-27 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001508586 SCV001714835 likely pathogenic not provided 2020-10-19 criteria provided, single submitter clinical testing PS3, PM2
Natera, Inc. RCV000029487 SCV001460201 uncertain significance Cystic fibrosis 2020-09-16 no assertion criteria provided clinical testing

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