Submissions for variant NM_000492.4(CFTR):c.3468G>A (p.Leu1156=)

gnomAD frequency: 0.00003  dbSNP: rs139729994

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046899	SCV000677604	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000046899	SCV000220434	likely pathogenic	Cystic fibrosis	2014-06-19	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000428306	SCV000227776	uncertain significance	not provided	2014-12-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000428306	SCV000521024	pathogenic	not provided	2020-06-02	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24243928, 18463704, 15619636, 12833420, 21152102, 14685937, 23457292, 23951356, 23974870, 10923036, 31036917)
Mendelics	RCV000046899	SCV000886300	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000046899	SCV000992332	pathogenic	Cystic fibrosis	2019-11-11	criteria provided, single submitter	clinical testing	Previously reported disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
CFTR-France	RCV001009370	SCV001169223	pathogenic	Cystic fibrosis; CFTR-related disorder	2018-01-29	criteria provided, single submitter	curation	when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046899	SCV001372314	pathogenic	Cystic fibrosis	2020-06-18	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3468G>A (p.Leu1156Leu) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site and one predicts the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions indicating that the variant causes exon-skipping leading to premature termination and truncation of CFTR (Zielendki_1994). The variant allele was found at a frequency of 4e-06 in 250770 control chromosomes (gnomAD). c.3468G>A has been reported in the literature in compound heterozygous individuals affected with Cystic Fibrosis (e.g. Claustres_2000, Zielendki_1994) while it was also reported in homozygous individuals affected with CBAVD and pancreatitis (e.g. Claustres_2017 & CFTR-France online database). These data indicate that the variant is likely to be associated with disease. Five ClinVar submitters including an expert panel (CFTR2) (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	RCV000046899	SCV002156625	uncertain significance	Cystic fibrosis	2022-08-02	criteria provided, single submitter	clinical testing	This sequence change affects codon 1156 of the CFTR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CFTR protein. This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with CFTR-related conditions (PMID: 10923036). ClinVar contains an entry for this variant (Variation ID: 53750). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000428306	SCV002525782	likely pathogenic	not provided	2021-08-04	criteria provided, single submitter	clinical testing	PP3, PP5, PM2, PM3_strong
Ambry Genetics	RCV000046899	SCV002612975	pathogenic	Cystic fibrosis	2021-07-30	criteria provided, single submitter	clinical testing	The c.3468G>A pathogenic mutation (also known as p.L1156L) is located in coding exon 21 of the CFTR gene. This variant results from a G to A substitution at nucleotide position 3468. This nucleotide substitution does not change the amino acid at codon 1156. However, this change occurs in the last base pair of coding exon 21, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in multiple individuals with cystic fibrosis in conjunction with a pathogenic mutation in CFTR by our laboratory. In one individual, this variant was confirmed to be in trans with a pathogenic mutation. In addition, this mutation (also referred to as 3600G>A) has been reported in patients with cystic fibrosis (Claustres M et al. Hum. Mutat., 2000;16:143-56; Lim MT et al. Arch. Dis. Child., 2014 Mar;99:197-202). In an expression mini-gene assay, this mutation produced no correctly-spliced CFTR RNA and protein in HEK293 cells (The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed September 14, 2017). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003474580	SCV004213502	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-11-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000428306	SCV004563665	pathogenic	not provided	2023-09-04	criteria provided, single submitter	clinical testing	The CFTR c.3468G>A; p.Leu1156= variant (rs139729994) is reported in the compound heterozygous state in individuals with cystic fibrosis (see links to CF databases). However, this variant has also been reported in the homozygous state in an individual with pancreatitis, and an individual with congenital bilateral absence of vas deferens (Claustres 2017, CFTR France Database). This variant is reported in ClinVar (Variation ID: 53750). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is a synonymous variant located in the last nucleotide of exon 21 (exon 18 for traditional numbering), and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Functional studies using a mini-gene assay showed this variant does not produce correctly spliced CFTR RNA and protein in HEK293 cells (CFTR2 database). Based on available information, this variant is considered to be pathogenic with varying clinical consequences. REFERENCES Link to CFTR2 database: http://cftr2.org/ Link to Cystic Fibrosis Mutation Database: http://www.genet.sickkids.on.ca/ Claustres M et al. CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. Hum Mutat. 2017 Oct;38(10):1297-1315. PMID: 28603918.
Natera, Inc.	RCV001826667	SCV002075829	pathogenic	CFTR-related disorder	2020-04-11	no assertion criteria provided	clinical testing