ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.355A>G (p.Ile119Val) (rs193922518)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000770760 SCV000052177 uncertain significance not specified 2019-02-26 criteria provided, single submitter clinical testing Variant summary: CFTR c.355A>G (p.Ile119Val) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain of 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 2.9e-05 in 276662 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.355A>G in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported in the literature. CFTR-France database reports one asymptomatic patient that is compound heterozygote for the variant and a CF-causing variant. Cystic Fibrosis Mutation Database reports that the variant was found in a (probable) CF patient whose other variant is as yet unidentified; patient is reported with recurrent chest infections but normal sweat tests. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV000498090 SCV000589584 uncertain significance not provided 2017-06-08 criteria provided, single submitter clinical testing The I119V variant in the CFTR gene has not been reported previously in the medical literature as a pathogenic variant, nor as a benign variant, to our knowledge. However, the I119V variant is reported as likely pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000052177.1; Landrum et al., 2016). The I119V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I119V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals, however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (N113I, E116K, E116Q, R117G, R117C, R117L, R117P, A120T, Y122H, Y122C) have been reported in the Human Gene Mutation Database in association with CFTR-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret I119V as a variant of uncertain significance.
Invitae RCV000029525 SCV000834080 uncertain significance Cystic fibrosis 2018-01-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 119 of the CFTR protein (p.Ile119Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs193922518, ExAC 0.002%). This variant has not been reported in the literature in individuals with CFTR-related disease. ClinVar contains an entry for this variant (Variation ID: 35870). 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, 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.

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