Submissions for variant NM_000492.4(CFTR):c.3484C>T (p.Arg1162Ter)

gnomAD frequency: 0.00004  dbSNP: rs74767530

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
American College of Medical Genetics and Genomics (ACMG)	RCV000007557	SCV000071403	pathogenic	Cystic fibrosis	2004-03-03	practice guideline	curation	Converted during submission to Pathogenic.
CFTR2	RCV000007557	SCV000071551	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508142	SCV000601102	pathogenic	not provided	2017-01-05	criteria provided, single submitter	clinical testing
Mendelics	RCV000007557	SCV000886180	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780138	SCV000917183	pathogenic	not specified	2018-03-14	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3484C>T (p.Arg1162X) 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 5.4e-05 in 276330 control chromosomes. The c.3484C>T variant has been reported in the literature in numerous individuals affected with Cystic Fibrosis and is considered a common pathogenic mutation (see e.g. Sosnay 2013, Gasparini 1991). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence, which showed the lack of full length CFTR protein and improper localization of the truncated form at the plasma membrane in cells from a homozygous patient (Sorio 2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001004500	SCV001163545	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007557	SCV001169253	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000007557	SCV001194084	pathogenic	Cystic fibrosis	2019-11-12	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.3484C>T(R1162*) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of this disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.3484C>T(R1162*) 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000508142	SCV001450027	pathogenic	not provided	2018-08-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508142	SCV001471508	pathogenic	not provided	2020-04-04	criteria provided, single submitter	clinical testing	The CFTR c.3484C>T; p.Arg1162Ter variant (rs74767530) has been reported in patients diagnosed with cystic fibrosis, and is often associated with pancreatic insufficiency (Gasparini 1991, Gasparini 1992, Ooi 2012, Sosnay 2013, CFTR2 database). This variant is reported in ClinVar (Variation ID: 7137), and is found in the general population with an overall allele frequency of 0.0057% (16/281996 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, the p.Arg1162Ter variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ Gasparini P et al. The search for south European cystic fibrosis mutations: identification of two new mutations, four variants, and intronic sequences. Genomics. 1991; 10(1):193-200. Gasparini P et al. Nine cystic fibrosis patients homozygous for the CFTR nonsense mutation R1162X have mild or moderate lung disease. J Med Genet. 1992; 29(8):558-62. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7.
Invitae	RCV000007557	SCV001589894	pathogenic	Cystic fibrosis	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1162*) 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 (rs74767530, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (CF) and is included in the American College of Medical Genetics (ACMG) panel of CF variants (PMID: 15371902, 23974870). ClinVar contains an entry for this variant (Variation ID: 7137). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000508142	SCV001714253	pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing
3billion	RCV000007557	SCV002058307	pathogenic	Cystic fibrosis	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000007137, PMID:2045102). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000057, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
DASA	RCV000007557	SCV002061273	pathogenic	Cystic fibrosis	2022-01-05	criteria provided, single submitter	clinical testing	The c.3484C>T;p.(Arg1162*) variant creates a premature translational stop signal in the CFTR gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 7137; PMID: 20301428; 21416780; 15994263; 11101688; 20301428; 21811577; 7526685) - PS4. The variant is present at low allele frequencies population databases (rs74767530 – gnomAD 0.004604%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg1162*) was detected in trans with a pathogenic variant(PMID: 21811577) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
Ambry Genetics	RCV000007557	SCV002613317	pathogenic	Cystic fibrosis	2020-12-01	criteria provided, single submitter	clinical testing	The p.R1162* pathogenic mutation (also known as c.3484C>T), located in coding exon 22 of the CFTR gene, results from a C to T substitution at nucleotide position 3484. This changes the amino acid from an arginine to a stop codon within coding exon 22. This mutation has been reported in the homozygous state in nine individuals with pancreatic insufficiency and mild to moderate pulmonary symptoms (Gasparini P et al. J. Med. Genet., 1992 Aug;29:558-62). This pathogenic mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Shahin WA et al. Springerplus, 2016 May;5:686). 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.
Fulgent Genetics, Fulgent Genetics	RCV002504763	SCV002815314	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-08-04	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000007557	SCV004100580	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473016	SCV004213310	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914818	SCV004728264	pathogenic	CFTR-related condition	2024-02-14	criteria provided, single submitter	clinical testing	The CFTR c.3484C>T variant is predicted to result in premature protein termination (p.Arg1162*). This variant has been repeatedly reported to be causative for cystic fibrosis (see for example Gasparini et al. 1991. PubMed ID: 2045102; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000007557	SCV000027758	pathogenic	Cystic fibrosis	1992-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000007557	SCV001622792	not provided	Cystic fibrosis		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000508142	SCV001743287	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000508142	SCV001954691	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000508142	SCV001974099	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831531	SCV002075834	pathogenic	CFTR-related disorders	2017-03-17	no assertion criteria provided	clinical testing