ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.164+1G>T (rs397508243)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000576651 SCV000677597 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Counsyl RCV000576651 SCV000796986 pathogenic Cystic fibrosis 2018-01-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000576651 SCV001363799 pathogenic Cystic fibrosis 2019-06-10 criteria provided, single submitter clinical testing Variant summary: CFTR c.164+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. One predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249608 control chromosomes (gnomAD). The variant, c.164+1G>T, has been reported in the literature in individuals affected with Cystic Fibrosis, idiopathic chronic pancreatitis or bronchiectasis (Estivill_1997, Audrezet_2008, Dorfman_2010, Pagin_2016, Sapiejka_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000576651 SCV001574870 likely pathogenic Cystic fibrosis 2018-08-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the CFTR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of cystic fibrosis (PMID: 26900683, 20059485). ClinVar contains an entry for this variant (Variation ID: 53305). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000576651 SCV000679329 not provided Cystic fibrosis no assertion provided literature only

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