ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.4003C>T (p.Leu1335Phe) (rs145545286)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000929 SCV001158022 uncertain significance not specified 2018-11-20 criteria provided, single submitter clinical testing The CFTR c.4003C>T; p.Leu1335Phe variant (rs145545286) is reported in the literature in the heterozygous state with an unknown second allele in individuals with a suspected diagnosis of cystic fibrosis, as well as in healthy carriers (Krenkova 2013, Picci 2010, Tabor 2014). This variant is reported in ClinVar (Variation ID: 53871), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 1335 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.4004T>C p.Leu1335Pro) has been reported in individuals with cystic fibrosis and is considered mildly pathogenic (Ahmed 2003, Raraigh 2018, CFTR2 database). However, given the lack of clinical and functional data, the significance of the p.Leu1335Phe variant is uncertain at this time. References: Link to CFTR2 database for p.Leu1335Pro: Ahmed N et al. Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas. Gut. 2003 Aug;52(8):1159-64. 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. Picci L et al. A 10-year large-scale cystic fibrosis carrier screening in the Italian population. J Cyst Fibros. 2010 Jan;9(1):29-35. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Tabor HK et al. Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. Am J Hum Genet. 2014 Aug 7;95(2):183-93.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577004 SCV000679394 not provided Cystic fibrosis no assertion provided literature only

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