ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.164+1G>T

dbSNP: rs397508243
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Total submissions: 8
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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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000576651 SCV001574870 pathogenic Cystic fibrosis 2024-01-20 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. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 11810271, 26900683). ClinVar contains an entry for this variant (Variation ID: 53305). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000576651 SCV002573835 likely pathogenic Cystic fibrosis 2022-09-05 criteria provided, single submitter curation This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_MOD, PS1_SUP, PM2_SUP, PM3_STR, PP4
Ambry Genetics RCV000576651 SCV002709339 likely pathogenic Cystic fibrosis 2022-06-15 criteria provided, single submitter clinical testing The c.164+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 2 of the CFTR gene. This variant was reported in one individual with bronchiectasis with a second CFTR variant; however, phase was not provided (Pagin A et al. PLoS One, 2016 Feb;11:e0149426). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Baylor Genetics RCV003473459 SCV004213554 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2023-03-02 criteria provided, single submitter clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000576651 SCV000679329 not provided Cystic fibrosis no assertion provided literature only

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