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

dbSNP: rs397508261

Total submissions: 10

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	pathogenic	not provided	2024-02-27	criteria provided, single submitter	clinical testing	The CFTR c.1680-877G>T variant (also known as 1811+1643G>T) has been reported in the published literature in several individuals affected with cystic fibrosis (CF) (PMIDs: 34782259 (2021), 30296588 (2018), 29970830 (2018), 28475858 (2017), 26574590 (2015), 22608296 (2012)). Experimental studies have shown that this variant activates a cryptic donor site that causes the inclusion of a 53 bp pseudo exon between exons 12 and 13 in the final CFTR mRNA and a frameshift in the coding sequence (p.Ala561Serfs*15). This results in complete loss of normal CFTR protein (PMID: 28475858 (2017)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic..
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046407	SCV001574927	pathogenic	Cystic fibrosis	2024-08-18	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