ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.4097T>C (p.Ile1366Thr) (rs200955612)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000630457 SCV000751413 uncertain significance Cystic fibrosis 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1366 of the CFTR protein (p.Ile1366Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs200955612, ExAC 0.009%). This variant has been reported in an individual affected with congenital bilateral absence of the vas defense (PMID: 21520337), and in an unaffected control individual (PMID: 11379874). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000630457 SCV000791936 uncertain significance Cystic fibrosis 2017-06-02 criteria provided, single submitter clinical testing
CFTR-France RCV001009486 SCV001169581 pathogenic CFTR-related disorders 2018-01-29 criteria provided, single submitter curation
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285637 SCV001472102 uncertain significance none provided 2020-08-13 criteria provided, single submitter clinical testing The CFTR c.4097T>C; p.Ile1366Thr variant (rs200955612) is reported in the literature in the heterozygous state in individuals affected with congenital bilateral absence of the vas deferens and also in healthy carriers (Le Marechal 2001, Steiner 2011). This variant is reported in ClinVar (Variation ID: 526019), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 1366 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.4097T>A; p.Ile1366Asn; c.4096A>T; p.Ile1366Phe) have been reported in individuals with cystic fibrosis (see link to CFTR2 database, Arslan 2020). However, given the lack of clinical and functional data, the significance of the p.Ile1366Thr variant is uncertain at this time. References: Link to CFTR2 database: Arslan AB et al. A Novel Pathogenic Variant of the CFTR Gene in a Patient with Cystic Fibrosis Phenotype-c.4096A?>?T. J Pediatr Genet. 2020;9(1):40-43. Le Marechal C et al. Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling. Hum Genet. 2001;108(4):290-298. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2012 Feb;33(2):456. Hum Mutat. 2011;32(8):912-920.
Natera, Inc. RCV000630457 SCV001454294 uncertain significance Cystic fibrosis 2020-09-16 no assertion criteria provided clinical testing

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