Submissions for variant NM_000492.4(CFTR):c.274G>T (p.Glu92Ter)

dbSNP: rs121908751

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007606	SCV000071538	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007606	SCV000696921	pathogenic	Cystic fibrosis	2017-07-31	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.274G>T (p.Glu92X) variant involves the alteration of a conserved nucleotide. One in silico tool predicts a damaging outcome for this variant. A functional study showed that it affects the 3 splice site of exon 4 and creates an in-frame stop codon and concluded this variant to determine pancreatic insufficiency (Will_JCI_1993). The variant of interest has not been found in a large, broad control population, ExAC in 0.0000047, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant was reported in multiple CF patients (Sosnay_Nature Genetics_2013, Will_JCI_1993). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics	RCV000007606	SCV000886217	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004423	SCV001163467	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV001009515	SCV001169610	pathogenic	Cystic fibrosis; CFTR-related disorder	2018-01-29	criteria provided, single submitter	curation	the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
Myriad Genetics, Inc.	RCV000007606	SCV001194021	pathogenic	Cystic fibrosis	2019-12-09	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.274G>T(E92*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.274G>T(E92*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007606	SCV001585090	pathogenic	Cystic fibrosis	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu92*) 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 (rs121908751, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 7512993, 23974870). ClinVar contains an entry for this variant (Variation ID: 7186). This variant disrupts the p.Arg117 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7525450, 15482777, 21783433, 22658665, 23974870, 24586523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007606	SCV002573831	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1, PS3_SUP, PM2_SUP, PM3_STR
Ambry Genetics	RCV000007606	SCV002752116	pathogenic	Cystic fibrosis	2022-08-22	criteria provided, single submitter	clinical testing	The p.E92* pathogenic mutation (also known as c.274G>T and c.406G>T) is located in coding exon 4 of the CFTR gene. This changes the amino acid from a glutamic acid to a stop codon within coding exon 4. Since this nucleotide is in the first position of coding exon 4, splicing effects have also been observed (Will K et al. J. Clin. Invest., 1994 Apr;93:1852-9; Will K et al. Hum. Mutat., 1995;5:210-20).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 08/22/2022). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Johns Hopkins Genomics, Johns Hopkins University	RCV000007606	SCV003839132	pathogenic	Cystic fibrosis	2022-11-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473036	SCV004213449	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-07-31	criteria provided, single submitter	clinical testing
OMIM	RCV000007606	SCV000027807	pathogenic	Cystic fibrosis	1994-04-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001826443	SCV002080112	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing