ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.4436G>A (p.Arg1479Lys) (rs1325117166)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000595527 SCV000708649 uncertain significance not provided 2018-07-20 criteria provided, single submitter clinical testing
Invitae RCV000805213 SCV000945161 uncertain significance Cystic fibrosis 2019-03-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 1479 of the CFTR protein (p.Arg1479Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CFTR-related disease. ClinVar contains an entry for this variant (Variation ID: 502054). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000853 SCV001157927 uncertain significance not specified 2018-10-04 criteria provided, single submitter clinical testing The CFTR c.4436G>A; p.Arg1479Lys variant, to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 502054). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 1479 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Arg1479Lys variant is uncertain at this time.
Ambry Genetics RCV001022475 SCV001184218 uncertain significance Inborn genetic diseases 2019-03-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV001000853 SCV001360542 uncertain significance not specified 2019-01-24 criteria provided, single submitter clinical testing Variant summary: The variant, CFTR c.4436G>A (p.Arg1479Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 245562 control chromosomes (gnomAD). 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.4436G>A in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance

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