Submissions for variant NM_000492.4(CFTR):c.3276C>A (p.Tyr1092Ter)

gnomAD frequency: 0.00003  dbSNP: rs121908761

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056379	SCV000071565	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
GeneDx	RCV000522700	SCV000616674	pathogenic	not provided	2018-02-28	criteria provided, single submitter	clinical testing	The Y1092X pathogenic variant in the CFTR gene has been reported previously as a cystic fibrosis-causing variant, accounting for approximately 0.2% of all cystic fibrosis mutant alleles (Tsui, 1992; Sosnay et al., 2013). The Y1092X variant has also been implicated in chronic pancreatitis and pancreatic insufficiency (Ockenga et al., 2000; Ooi and Durie, 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y1092X variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016). We interpret Y1092X as a pathogenic variant.
Eurofins Ntd Llc (ga)	RCV000522700	SCV000854906	pathogenic	not provided	2018-08-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000056379	SCV000886190	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763157	SCV000893744	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-01-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781257	SCV000919166	pathogenic	not specified	2018-12-13	criteria provided, single submitter	clinical testing	Variant summary: The variant CFTR c.3276C>A (p.Tyr1092X) 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. The variant allele was found at a frequency of 1.2e-05 in 245972 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Bozon_1994, DeBraekeleer_1998, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories 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.
Baylor Genetics	RCV001004305	SCV001163182	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056379	SCV001169281	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000056379	SCV001194063	pathogenic	Cystic fibrosis	2019-12-09	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.3276C>A(Y1092*) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID 18456578, 1284534 and 23974870. Classification of NM_000492.3(CFTR):c.3276C>A(Y1092*) 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000522700	SCV001446980	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056379	SCV001584104	pathogenic	Cystic fibrosis	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1092*) 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). 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 premature translational stop signal has been observed in individual(s) with cystic fibrosis and chronic pancreatitis. A second, pathogenic, CFTR variant was not reported in this individual (PMID: 10950058, 12815607, 15480987, 18456578, 21416780, 23974870, 24586523, 25910067). ClinVar contains an entry for this variant (Variation ID: 38728). 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000056379	SCV001711960	pathogenic	Cystic fibrosis	2021-06-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000056379	SCV002612074	pathogenic	Cystic fibrosis	2021-05-09	criteria provided, single submitter	clinical testing	The p.Y1092* pathogenic mutation (also known as c.3276C>A), located in coding exon 20 of the CFTR gene, results from a C to A substitution at nucleotide position 3276. This changes the amino acid from a tyrosine to a stop codon within coding exon 20. This pathogenic mutation was first described in an individual with pancreatic insufficient cystic fibrosis in conjunction with p.F508del (Bozon D et al. Hum. Mutat., 1994;3:330-2). This 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	RCV003473243	SCV004213375	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000522700	SCV004563283	pathogenic	not provided	2023-03-07	criteria provided, single submitter	clinical testing	The CFTR c.3276C>A; p.Tyr1092Ter variant (rs121908761) has been reported in the medical literature in several individuals with pancreatic insufficient cystic fibrosis (Castellani 2008, De Braekeleer 1998, Sosnay 2013). The variant is reported in ClinVar (Variation ID: 38728) and is reported in the general population with an overall allele frequency of 0.0018% (5/282,504 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Castellani C et al. Consensus on the Use and Interpretation of Cystic Fibrosis Mutation Analysis in Clinical Practice. J Cyst Fibros. 2008 May;7(3):179-96. PMID: 18456578. De Braekeleer M et al. Phenotypic Variability in Five Cystic Fibrosis Patients Compound Heterozygous for the Y1092X Mutation. Hum Hered. May-Jun 1998;48(3):158-62. PMID: 9618063. Sosnay PR et al. Defining the Disease Liability of Variants in the Cystic Fibrosis Transmembrane Conductance Regulator Gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870.
OMIM	RCV000056379	SCV000143751	pathogenic	Cystic fibrosis	1993-01-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000522700	SCV001739694	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000522700	SCV001955636	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000522700	SCV001967151	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831621	SCV002083621	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001831621	SCV004727965	pathogenic	CFTR-related disorder	2024-03-02	no assertion criteria provided	clinical testing	The CFTR c.3276C>A variant is predicted to result in premature protein termination (p.Tyr1092*). This variant has been reported in the compound heterozygous state in multiple individuals with cystic fibrosis (Bozon et al. 1994. PubMed ID: 7517268; Scotet et al. 2003. PubMed ID: 12815607; Sosnay et al. 2013. PubMed ID: 23974870; Ziętkiewicz et al. 2014. PubMed ID: 24586523; Lucarelli et al. 2015. PubMed ID: 25910067; Raraigh et al. 2022. PubMed ID: 34782259) and has been observed to co-segregate with disease in a large French Canadian family (De Braekeleer et al. 1998. PubMed ID: 9618063). It has also been reported as a single heterozygous variant in a patient with chronic pancreatitis (Ockenga et al. 2000. PubMed ID: 10950058). A different nucleotide substitution with the same predicted effect (c.3276C>G, p.Tyr1092*) has also been reported in multiple individuals with cystic fibrosis (Schrijver et al. 2005. PubMed ID: 16049310; Raraigh et al. 2022. PubMed ID: 34782259) and an absence of chloride channel function has been noted in in vitro studies of biopsied tissue samples and primary cell cultures from patients heterozygous for both the p.Phe508del and p.Tyr1092* variants (Hirtz et al. 2004. PubMed ID: 15480987; Awatade et al. 2015. PubMed ID: 26137539). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. Taken together, this variant is interpreted as pathogenic.