ClinVar Miner

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

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Total submissions: 7
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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 RCV000595140 SCV000696971 likely benign not specified 2021-03-22 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. 4/4 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 variant, 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. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance, likely benign and 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
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283285 SCV001159203 likely benign none provided 2020-02-27 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000007649 SCV001435188 benign Cystic fibrosis criteria provided, single submitter research The heterozygous c.3469-20T>C variant in CFTR has been reported in at least 3 individuals with cystic fibrosis without another variant identified in the gene (PMID: 10869121, 20551465, 21520337), and has been identified in >1% of South Asian chromosomes and 7 homozygotes by ExAC ( In summary, this variant meets criteria to be classified as benign for autosomal recessive cystic fibrosis.
Invitae RCV000007649 SCV001731520 benign Cystic fibrosis 2020-12-08 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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