ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2982C>A (p.Phe994Leu)

gnomAD frequency: 0.00003  dbSNP: rs373561883
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001048747 SCV001178896 uncertain significance Cystic fibrosis 2019-07-17 criteria provided, single submitter clinical testing The p.F994L variant (also known as c.2982C>A), located in coding exon 18 of the CFTR gene, results from a C to A substitution at nucleotide position 2982. The phenylalanine at codon 994 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001048747 SCV001212766 uncertain significance Cystic fibrosis 2021-08-27 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 994 of the CFTR protein (p.Phe994Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs373561883, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. 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 tolerated. 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.
Genome-Nilou Lab RCV001048747 SCV002027478 uncertain significance Cystic fibrosis 2021-09-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001824914 SCV002074402 uncertain significance not specified 2022-01-22 criteria provided, single submitter clinical testing Variant summary: CFTR c.2982C>A (p.Phe994Leu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251092 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2982C>A in individuals affected with Cystic Fibrosis/CFTR-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. 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.
Natera, Inc. RCV001827193 SCV002083572 uncertain significance CFTR-related disorders 2018-11-02 no assertion criteria provided clinical testing

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