Submissions for variant NM_000492.4(CFTR):c.2290C>T (p.Arg764Ter)

gnomAD frequency: 0.00001  dbSNP: rs121908810

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056363	SCV000071555	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Mendelics	RCV000056363	SCV000886219	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759035	SCV000888077	pathogenic	not provided	2017-10-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004473	SCV001163518	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056363	SCV001169531	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000056363	SCV001194018	pathogenic	Cystic fibrosis	2019-12-09	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.2290C>T(R764*) 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 8956039 and 23974870. Classification of NM_000492.3(CFTR):c.2290C>T(R764*) 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056363	SCV001337813	pathogenic	Cystic fibrosis	2020-01-13	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2290C>T (p.Arg764X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.4e-06 in 226822 control chromosomes. c.2290C>T has been well reported in the literature in multiple individuals affected with Cystic Fibrosis (example, Hughes_1996, Roth_2011, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in NMRD (nonsense-mediated RNA decay) (Sheridan_2011). Three clinical diagnostic laboratories and one expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056363	SCV001580386	pathogenic	Cystic fibrosis	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg764*) 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 (rs121908810, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis or congenital bilateral absence of the vas deferens (PMID: 8956039, 21097845, 21520337, 23974870, 27086061, 28544683, 28603918). ClinVar contains an entry for this variant (Variation ID: 53471). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000056363	SCV002736326	pathogenic	Cystic fibrosis	2022-08-17	criteria provided, single submitter	clinical testing	The p.R764* pathogenic mutation (also known as c.2290C>T), located in coding exon 14 of the CFTR gene, results from a C to T substitution at nucleotide position 2290. This changes the amino acid from an arginine to a stop codon within coding exon 14. In one study, this mutation was described in 3 individuals with classic cystic fibrosis; one individual was homozygous for this alteration (Strandvik B et al. Genet. Test., 2001;5:235-42). This pathogenic mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). 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.
Baylor Genetics	RCV003473480	SCV004213437	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831746	SCV002080728	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001831746	SCV004750687	pathogenic	CFTR-related disorder	2023-11-09	no assertion criteria provided	clinical testing	The CFTR c.2290C>T variant is predicted to result in premature protein termination (p.Arg764*). This variant has been reported in several individuals with CFTR-related disorders (cftr2.org; Hughes et al. 1996. PubMed ID: 8956039; Sheridan et al. 2010. PubMed ID: 21097845; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.0042% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117232511-C-T). Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.