ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.598T>A (p.Phe200Ile)

dbSNP: rs397508766
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000507508 SCV000601127 uncertain significance not specified 2017-06-19 criteria provided, single submitter clinical testing
CFTR-France RCV001009495 SCV001169590 pathogenic CFTR-related disorder 2018-01-29 criteria provided, single submitter curation
Genome-Nilou Lab RCV001705707 SCV001822014 likely pathogenic Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV001705707 SCV005042907 likely pathogenic Cystic fibrosis criteria provided, single submitter clinical testing The missense c.598T>Ap.Phe200Ile variant in CFTR gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Cystic fibrosis Dorfman et al., 2010. This variant is reported with the allele frequency of 0.0004% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic. However, study of the variant in multiple affected individuals and its functional impact on the protein is required to determine the pathogenicity of the variant. The amino acid Phe at position 200 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Phe200Ile in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is located in a mutational hot spot. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001705707 SCV005381404 likely pathogenic Cystic fibrosis 2024-08-05 criteria provided, single submitter clinical testing Variant summary: CFTR c.598T>A (p.Phe200Ile) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251450 control chromosomes (gnomAD). c.598T>A has been reported in the literature in an individual affected with CBAVD (Steiner_2011). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 3% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 31674704, 38388235, 21520337). ClinVar contains an entry for this variant (Variation ID: 54021). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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