ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3469-17T>C (rs199630678)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001082947 SCV000074913 benign Cystic fibrosis 2020-12-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000245337 SCV000304489 likely benign not specified criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000245337 SCV000601101 uncertain significance not specified 2017-05-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000245337 SCV000603031 likely benign not specified 2019-04-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726749 SCV000702762 uncertain significance not provided 2018-03-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000245337 SCV000919176 uncertain significance not specified 2020-10-15 criteria provided, single submitter clinical testing Variant summary: CFTR c.3469-17T>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 0.00059 in 250506 control chromosomes, predominantly at a frequency of 0.0033 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0033 vs 0.013), allowing no conclusion about variant significance. c.3469-17T>C has been reported in the literature in individuals affected with Cystic Fibrosis and azoospermia (e.g. Audrezet_1993, Claustres_2000, Scotet_2003, Gallati_2009, Soltysova_2018) but it was also reported in healthy controls (e.g. Bergougnoux_2015). 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 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and two ClinVar submitters (evaluation after 2014) cite it as benign/likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until additional data of clinical and/or functional importance becomes available.

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