Submissions for variant NM_000492.4(CFTR):c.274G>A (p.Glu92Lys)

dbSNP: rs121908751

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007601	SCV000071498	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000007601	SCV000486948	pathogenic	Cystic fibrosis	2016-09-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007601	SCV000696920	pathogenic	Cystic fibrosis	2017-06-13	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.274G>A (p.Glu92Lys) variant involves the alteration of a conserved nucleotide located in the ABC transporter type 1, transmembrane domain (InterPro). The variant affects the first nucleotide in exon 4. 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 117032 control chromosomes. The variant has been reported in numerous CF alleles in the literature, and functional in vitro analysis has shown the variant to result in defective CFTR processing and <10% chloride transport (Sosnay_2013, Van Goor_2014) compared to WT. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
CFTR-France	RCV001009395	SCV001169248	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
CeGaT Center for Human Genetics Tuebingen	RCV001093484	SCV001250498	pathogenic	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001093484	SCV001449902	pathogenic	not provided	2017-09-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007601	SCV001582019	pathogenic	Cystic fibrosis	2024-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 92 of the CFTR protein (p.Glu92Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis, pancreatic insufficiency and congenital bilateral absence of the vas deferens (CBAVD) (PMID: 10875853, 18178635, 29504914). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7181). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CFTR function (PMID: 18306312, 23891399, 23924900, 28448979). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000007601	SCV001810338	pathogenic	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007601	SCV002747574	pathogenic	Cystic fibrosis	2022-07-26	criteria provided, single submitter	clinical testing	The p.E92K pathogenic mutation (also known as c.274G>A and 406G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 274. This change occurs in the first base pair of coding exon 4. The glutamic acid at codon 92 is replaced by lysine, an amino acid with some similar properties. This mutation was identified in the homozygous state in a child with cystic fibrosis, elevated sweat chloride level, pancreatic sufficiency and history of Pseudomonas infection (Stanke F et al. J Med Genet. 2008;45(1):47-54). 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 07/26/2022). This variant has <25% of wild type quantity and <10% of wild type function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 07/26/2022; Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). In addition, in vitro functional studies in FRT cells with this variant showed little to no mature CFTR protein (Van Goor F et al. J Cyst Fibros. 2014;13(1):29-36) . Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003473033	SCV004213336	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-11-18	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007601	SCV005900139	pathogenic	Cystic fibrosis	2025-03-04	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PS3,PM5,PM2_SUP,PP3,PP4
OMIM	RCV000007601	SCV000027802	pathogenic	Cystic fibrosis	1993-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001831545	SCV002080111	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing