ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1365G>T (p.Ala455=) (rs79074685)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000173698 SCV000224842 uncertain significance not provided 2016-01-12 criteria provided, single submitter clinical testing
Invitae RCV000173698 SCV000751425 likely benign not provided 2018-02-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781283 SCV000919196 likely benign not specified 2018-06-07 criteria provided, single submitter clinical testing Variant summary: CFTR c.1365G>T (p.Ala455Ala) alters a non-conserved nucleotide resulting in a synonymous change in exon 10 of the gene. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0071 in 238136 control chromosomes (in gnomAD). The observed variant frequency in the African (0.02640) and European Finnish (0.02228) subpopulations was roughly 2-fold of the expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.013). Furthermore, the variant allele was indicated to be found with an even higher occurrence in the Japanese control population (in HGVD); i.e. with a frequency of 0.1348 (including 19 homozygotes), that would suggest this variant is likely a benign polymorphism. However, CFTR exon 10 and its flanking regions are known to have sequence identity with similar sequences in the human genome (that are located on several other chromosomes), therefore variants described in this exon could be variations observed in ectopic similar sequences. Previous reports also suggested that several variants described in exon 10 and its flanking regions may in fact be ectopic variations (PMID: 23261175, 25956447). As the technology utilized for genomic databases does not rule out pseudogene interference in this region, these data may not be reliable for assessing variant frequency. To our knowledge, no occurrence of c.1365G>T in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Another variant, c.1365G>A, that affects the same nucleotide and leads to the same codon effect (p.Ala455Ala) was classified as likely benign by our laboratory. Based on the evidence outlined above, the variant of interest was classified as likely benign.

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