ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3469-20T>C (rs373002889)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000595140 SCV000696971 likely benign not specified 2019-08-08 criteria provided, single submitter clinical testing Variant summary: CFTR c.3469-20T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 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 0.0015 in 250478 control chromosomes, predominantly at a frequency of 0.012 within the South Asian subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency is close to the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Cystic Fibrosis (0.012 vs 0.013), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The varianrt, c.3469-20T>C, has been reported in the literature in individuals affected with Cystic Fibrosis and idiopathic chronic pancreatitis (Kabra_2000, Midha_2010, Steiner_2011, Claustres_2017). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. The variant was also found in a French CF patient as a complex allele in cis with a pathogenic CFTR variant c.3197G>A (p.Arg1066His), suggesting a possibly non-pathogenic role for the variant of interest (Claustres_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submission (evaluation after 2014) classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000595140 SCV000709545 benign not specified 2017-06-22 criteria provided, single submitter clinical testing
Mendelics RCV000007649 SCV001137493 uncertain significance Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
OMIM RCV000007649 SCV000027850 pathogenic Cystic fibrosis 2000-07-17 no assertion criteria provided literature only

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