Submissions for variant NM_000492.4(CFTR):c.1680-886A>G

gnomAD frequency: 0.00003  dbSNP: rs397508266

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046417	SCV000071568	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046417	SCV000074430	pathogenic	Cystic fibrosis	2024-01-22	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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with CFTR-related conditions (PMID: 23974870, 25122143). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1679+1.6kbA>G or c.1811+1.6kbA>G. ClinVar contains an entry for this variant (Variation ID: 53338). Studies have shown that this variant results in an insertion of 49 bp from intron 12 into the transcript and introduces a premature termination codon (PMID: 7534040). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000724668	SCV000700815	pathogenic	not provided	2017-02-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763576	SCV000894415	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781239	SCV000919144	pathogenic	not specified	2017-11-16	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.1679+1634A>G variant involves the alteration of a non-conserved intronic nucleotide and 4/5 splice prediction tools predict a significant impact on normal splicing (creation of a novel splicing donor site). cDNA studies proved the aberrant splicing (Chillon_1995). This variant is absent in 30882 control chromosomes (gnomAD). This variant has been reported in many affected individuals. Functional studies showed that individuals with genotype deltaF508/c.1679+1634A>G have only 1%-3% of normal CFTR mRNA. This loss of 97% of normal CFTR mRNA must be responsible for the pancreatic insufficiency and for the severe CF phenotype in these patients (Chillion_1995 and Sosnay_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics	RCV000046417	SCV001137480	pathogenic	Cystic fibrosis	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004263	SCV001163139	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000046417	SCV001169393	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000724668	SCV002563975	pathogenic	not provided	2019-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000046417	SCV002711001	pathogenic	Cystic fibrosis	2022-04-04	criteria provided, single submitter	clinical testing	The c.1680-886A>G (also known as c.1679+1634A>G and 1811+1.6kbA>G) pathogenic mutation results from an A to G substitution 886 nucleotides upstream from coding exon 13 of the CFTR gene. This pathogenic mutation creates a significant reduction in the amount of CFTR mRNA and individuals identified with this alteration in trans with another severe pathogenic alteration were demonstrated to have pancreatic insufficiency (Chillon M et al. Am J Hum Genet. 1995;56:623-629). This pathogenic mutation was further described in 11 compound heterozygotes and 2 homozygous individuals, all who presented with elevated sweat chloride levels, severe pulmonary manifestations, and pancreatic insufficiency (Reboul MP et al. J Med Genet. 2002;39(11):e73). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000724668	SCV003853542	pathogenic	not provided	2021-04-05	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000046417	SCV003927249	pathogenic	Cystic fibrosis	2023-04-14	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
PreventionGenetics, part of Exact Sciences	RCV001027897	SCV004111926	pathogenic	CFTR-related disorder	2023-06-14	criteria provided, single submitter	clinical testing	The CFTR c.1680-886A>G variant is predicted to interfere with splicing. **Use**, which is predicted to interfere with splicing. This variant, also referred to as c.1679+1634A>G, c.1679+1.6kbA>G, or 1811+1.6kb A-->G, results in introduction of a 49bp exon between exons 12 and 13 and has previously been reported to be causative for Cystic Fibrosis (reported as a cryptic exon between exons 11 and 12 in Chillón et al. 1995 PubMed ID: 7534040; Sosnay et al. 2013. PubMed ID: 23974870; Steiner et al. 2011. PubMed ID: 21520337). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Natera, Inc.	RCV001027897	SCV001190620	pathogenic	CFTR-related disorder	2019-05-20	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000724668	SCV001957453	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000724668	SCV001963292	pathogenic	not provided		no assertion criteria provided	clinical testing