ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1680-877G>T

dbSNP: rs397508261
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000046407 SCV000677592 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Counsyl RCV000046407 SCV000485916 likely pathogenic Cystic fibrosis 2016-03-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000046407 SCV000696867 pathogenic Cystic fibrosis 2023-03-22 criteria provided, single submitter clinical testing Variant summary: CFTR c.1680-877G>T (also known as c.1679+1643G>T and 1811+1643G>T in publication and database) is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates a 5 donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and this variant results in creating a deep intronic donor and the inclusion of a 53 bp pseudoexon between exons 12 and 13 in the final processed mRNA (p.Ala561Serfs*15) (Lee_2017). The variant was absent in 31352 control chromosomes (gnomAD). c.1680-877G>T has been reported in the literature in compound heterozygous and homozygous individuals affected with Cystic Fibrosis (Schrijver_2016, Lee_2017, Raraigh_2022). These data indicate that the variant may be associated with disease. Six ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=4) and likely pathogenic (n=2), including CFTR2 classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759031 SCV000888072 likely pathogenic not provided 2018-04-27 criteria provided, single submitter clinical testing
Invitae RCV000046407 SCV001574927 pathogenic Cystic fibrosis 2023-12-10 criteria provided, single submitter clinical testing This sequence change falls in intron 12 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. This variant is present in population databases (rs397508261, gnomAD 0.1%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 26708955, 28475858, 29970830). This variant is also known as c.1679+1643G>T. ClinVar contains an entry for this variant (Variation ID: 53331). Studies have shown that this variant alters CFTR gene expression (PMID: 28475858). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000759031 SCV001714832 pathogenic not provided 2021-12-27 criteria provided, single submitter clinical testing PP5, PM2, PS3
Ambry Genetics RCV000046407 SCV002712835 pathogenic Cystic fibrosis 2022-12-20 criteria provided, single submitter clinical testing The c.1680-877G>T intronic pathogenic mutation (also known as c.1679+1643G>T and 1811+1643G>T) results from a G to T substitution 877 nucleotides upstream from coding exon 13 in the CFTR gene. In our clinical cohort, this alteration has been detected in the homozygous state in a few apparently unrelated individuals reported to have clinical presentations of cystic fibrosis (CF). This alteration was also identified in trans with p.F508del in an individual with CF; RNA studies of this individual's primary nasal epithelia cells revealed that this alteration resulted in an aberrant transcript with 53 extra nucleotides. The aberrant transcript was in lower abundance than the p.F508del transcript, suggestive of non-sense mediated decay. Consistent with this observation, a minigene bearing this alteration showed a complete loss of CFTR protein in HEK293 cells (Lee M et al. Am. J. Hum. Genet., 2017 May;100:751-765). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences RCV004537225 SCV004116935 likely pathogenic CFTR-related disorder 2022-11-23 criteria provided, single submitter clinical testing The CFTR c.1680-877G>T variant is predicted to interfere with splicing. This variant is predicted to possibly introduce a novel splice site (Alamut Visual Plus v1.6.1). This variant has been reported in individuals with autosomal recessive cystic fibrosis (Schrijver et al. 2016. PubMed ID: 26708955; https://cftr2.org/). This variant is also known as 1811+1643G>T and c.1679+1643G>T. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In summary, we classify this variant as likely pathogenic.
Baylor Genetics RCV003473462 SCV004213380 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2023-09-19 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000046407 SCV004812064 pathogenic Cystic fibrosis 2023-05-16 criteria provided, single submitter clinical testing Criteria applied: PS3,PM3_STR,PM2_SUP,PP3; Identified as compund heterozygous with NM_000492.4:c.1521_1523del

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