ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.853A>T (p.Ile285Phe) (rs151073129)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000598331 SCV000697048 benign not specified 2021-01-22 criteria provided, single submitter clinical testing Variant summary: CFTR c.853A>T (p.Ile285Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. In contrast, a recently published in-silico tools based consensus classifier has predicted this variant to have a neutral impact (Michels_2019). The variant allele was found at a frequency of 0.00043 in 280644 control chromosomes, predominantly at a frequency of 0.0046 within the African subpopulation in the gnomAD database, including 1 homozygote. The combined allele frequency of the two most frequent pathogenic CF variants in Africans (i.e. c.2988+1G>A and p.F508del) that are found in up to 60% of all carriers (see in PMID 21474639) is 0.0038 in the gnomAD database. Therefore, the allele frequency of c.853A>T alone is much higher than combined frequency of the two most common pathogenic variants in the same subpopulation, supporting a benign role for this variant. The variant, c.853A>T, has been reported in the literature in an individual with chronic respiratory problems and a non-informative genotype (example, Schrijver 2005) and in an individual reportedly affected with Cystic Fibrosis also with a non-informative genotype (example, Pereira 2019). It was also reported in trans with a large CFTR promoter deletion in a presumably unaffected mother of a CF proband. The molecular diagnosis of CF in the proband was attributed to two other variants, namely the promoter deletion inherited from the mother and c.2988+1G>A inherited from the father (Hantash_2006). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=2)/benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000598331 SCV000700536 likely benign not specified 2017-06-23 criteria provided, single submitter clinical testing
Mendelics RCV000029547 SCV001137469 benign Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000029547 SCV001597830 likely benign Cystic fibrosis 2020-11-26 criteria provided, single submitter clinical testing

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