ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.4004T>C (p.Leu1335Pro) (rs397508658)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000047055 SCV000924276 pathogenic Cystic fibrosis 2017-12-08 reviewed by expert panel research
Illumina Clinical Services Laboratory,Illumina RCV000047055 SCV000466527 uncertain significance Cystic fibrosis 2016-07-27 criteria provided, single submitter clinical testing The CFTR c.4004T>C (p.Leu1335Pro) variant is a missense variant that has been reported in four studies, where it was found in a heterozygous state in a total of six individuals with cystic fibrosis; no second variant was identified in these individuals (Scotet et al. 2003; Krenkova et al. 2009; Dorfman et al. 2010; Krenkova et al. 2013). Control data are unavailable for the p.Leu1335Pro variant, which is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium despite being found in a region of good sequencing coverage. The variant is thus presumed to be rare. The evidence for this variant is limited. Therefore, the p.Leu1335Pro variant is classified as a variant of unknown significance but suspicious for pathogenicity for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl RCV000047055 SCV000800815 pathogenic Cystic fibrosis 2018-05-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781251 SCV000919159 pathogenic not specified 2018-03-22 criteria provided, single submitter clinical testing Variant summary: CFTR c.4004T>C (p.Leu1335Pro) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276844 control chromosomes. c.4004T>C has been reported in the literature in individuals affected with Cystic Fibrosis, but in most of these cases without a second allele specified or sweat chloride concentrations. Two reported pancreatic sufficient CF patients were compound heterozygous for the variant and the deltaF508 pathogenic allele with elevated sweat chloride levels (Rose 2009, Ivanov 2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. However, the CFTR2 database classifies the variant as CF-causing based on 18 patients in the database with an average sweat chloride level of 82 mEq/L. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000047055 SCV001587413 pathogenic Cystic fibrosis 2020-02-14 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1335 of the CFTR protein (p.Leu1335Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with cystic fibrosis (PMID: 29504914, 19445912, 23974870). ClinVar contains an entry for this variant (Variation ID: 53872). This variant has been reported to affect CFTR protein function (PMID: 29805046). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV000047055 SCV001454291 pathogenic Cystic fibrosis 2020-09-16 no assertion criteria provided clinical testing

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