Submissions for variant NM_000492.4(CFTR):c.2491G>T (p.Glu831Ter)

gnomAD frequency: 0.00002  dbSNP: rs397508387

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056366	SCV000071537	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Mendelics	RCV000056366	SCV000886229	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
CFTR-France	RCV000056366	SCV001169563	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197557	SCV001368336	pathogenic	Hereditary pancreatitis	2019-10-22	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056366	SCV001586217	pathogenic	Cystic fibrosis	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu831*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs397508387, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with CFTR-related disease (PMID: 20949073, 23974870, 25910067). This variant is also known as c.2623G>T. ClinVar contains an entry for this variant (Variation ID: 53501). 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.
Ambry Genetics	RCV000056366	SCV002741026	pathogenic	Cystic fibrosis	2021-11-30	criteria provided, single submitter	clinical testing	The c.2491G>T pathogenic mutation (also known as p.E831*), located in coding exon 15 of the CFTR gene, results from a G to T substitution at nucleotide position 2491. The glutamic acid at codon 831 is replaced by a stop codon. However, this change occurs in the first base pair of coding exon 15, which means it may have some effect on normal mRNA splicing. This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 11/30/2021). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. In vitro studies show that this alteration may result in alternative splicing (Hinzpeter A et al. PLoS Genet, 2010 Oct;6:; Sharma N et al. PLoS Genet, 2018 11;14:e1007723). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003473487	SCV004213275	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031498	SCV005673362	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-04-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000056366	SCV000220270	pathogenic	Cystic fibrosis	2015-10-09	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826638	SCV002080758	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001826638	SCV004105954	pathogenic	CFTR-related disorder	2024-06-21	no assertion criteria provided	clinical testing	The CFTR c.2491G>T variant is predicted to result in premature protein termination (p.Glu831*). This variant was previously reported in multiple individuals with cystic fibrosis (see, for example, Hughes et al. 1996. PubMed ID: 8956039; Sosnay et al. 2013. PubMed ID: 23974870, supplementary data; Lucarelli et al. 2015. PubMed ID: 25910067). This nucleotide change occurs at the first nucleotide position in exon 15. Functional analysis indicated that this nucleotide change leads to generation of three isoforms: aberrant splicing of CFTR and an isoform with an in-frame deletion of exon 15; an isoform with a protein truncation at p.Glu831*; and an isoform harboring a single amino acid deletion of p.Glu831 (Sharma et al. 2018. PubMed ID: 30444886). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117234984-G-T) and has been reported as pathogenic by multiple outside laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/53501/). Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.