Submissions for variant NM_000492.4(CFTR):c.3196C>T (p.Arg1066Cys)

gnomAD frequency: 0.00006  dbSNP: rs78194216

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007582	SCV000071516	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007582	SCV000696955	pathogenic	Cystic fibrosis	2017-06-19	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.3196C>T (p.Arg1066Cys) missense variant located in the ABC transporter type 1, transmembrane domain (via InterPro) involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools.This variant was found in 9/223414 control chromosomes at a frequency of 0.0000403, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). In literature, this variant is recurrently reported in CF patients, primarily in compound heterozygous state with p.Phe508del and is regarded as a severe mutation with consistent clinical and functional outcome (Fanen_1992, Fanen_1997, Sosnay_2013, Van Goor_2013, Dupuis_2015). In a large study that included CF patients from Europe and North America, the allele frequency of this variant was 0.15% (122/79,392 CF chromosomes) (Sosnay_2013). It leads to defective CFTR processing and the drug, ivacaftor, was unable to increase chloride channel function in an in vitro assay (Van Goor_2013), implicating therapeutic importance in patients carrying this variant. Other missense changes at the same residue, namely R1066H, R1066S, and R1066L, have been reported in association with CF indicating that R1066 residue is a mutational hot-spot. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000723839	SCV000700672	pathogenic	not provided	2017-06-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000007582	SCV000886182	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001063	SCV001158186	pathogenic	not specified	2019-02-21	criteria provided, single submitter	clinical testing	The CFTR c.3196C>T; p.Arg1066Cys variant (rs78194216) is reported to cause pancreatic insufficient (PI) cystic fibrosis (CF) in individuals homozygous for this variant or compound heterozygous with a second PI CF-causing variant on the opposite chromosome (CFTR2 database, Casals 1997, Liang 1998). Functional analysis shows that p.Arg1066Cys results in a nonfunctional CFTR protein (Sosnay 2013). This variant is reported as pathogenic in ClinVar (Variation ID: 7162). It is found in the general population with an overall allele frequency of 0.003% (8/250882 alleles) in the Genome Aggregation Database. The arginine at codon 1066 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES CFTR2 database: https://cftr2.org/ Casals T et al. Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: study of 19 heterozygous and 2 homozygous patients. Hum Mutat. 1997;10(5):387-92. Liang MH et al. Cystic fibrosis in a Puerto Rican female homozygous for the R1066C mutation. J Med Genet. 1998 Jan;35(1):84-5. 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.
Baylor Genetics	RCV001004298	SCV001163174	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000007582	SCV001167242	pathogenic	Cystic fibrosis	2019-10-14	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
CFTR-France	RCV000007582	SCV001169278	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000007582	SCV001194230	pathogenic	Cystic fibrosis	2019-11-12	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.3196C>T(R1066C) 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, 9375855 and 9374552. Classification of NM_000492.3(CFTR):c.3196C>T(R1066C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007582	SCV001584342	pathogenic	Cystic fibrosis	2024-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1066 of the CFTR protein (p.Arg1066Cys). This variant is present in population databases (rs78194216, gnomAD 0.006%). This missense change has been observed in individuals with cystic fibrosis or congenital absence of the vas deferens (PMID: 10923036, 11883825, 15084222, 17331079, 21520337, 23302613, 23974870). This variant is also known as 3328C>T. ClinVar contains an entry for this variant (Variation ID: 7162). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 8662892, 8702904, 9374552, 15480987, 23891399, 23974870). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000723839	SCV001714245	pathogenic	not provided	2020-12-11	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000723839	SCV002009131	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
DASA	RCV000007582	SCV002318973	pathogenic	Cystic fibrosis	2022-03-25	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 9374552) - PS3. The c.3196C>T;p.(Arg1066Cys) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID 7162; PMID: 9375855; PMID: 25697318; PMID: 27022295) -PS4. The variant is present at low allele frequencies population databases (rs78194216 – gnomAD 0.0003189%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. The p.(Arg1066Cys) was detected in trans with a pathogenic variant (PMID: 9375855) - PM3. Pathogenic missense variant in this residue have been reported (Clinvar ID 7158) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 9375855 - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic
Ambry Genetics	RCV000007582	SCV002609432	pathogenic	Cystic fibrosis	2022-06-14	criteria provided, single submitter	clinical testing	The p.R1066C pathogenic mutation (also known as c.3196C>T and 3328C>T), located in coding exon 20 of the CFTR gene, results from a C to T substitution at nucleotide position 3196. The arginine at codon 1066 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this mutation was identified in 21 individuals with a severe phenotype, including pancreatic insufficiency and moderate to severe pulmonary disease. Nineteen individuals were compound heterozygous for a pathogenic mutation on the other allele and two unrelated individuals were homozygous for this mutation (Casals T et al. Hum. Mutat., 1997;10:387-92). This mutation results in defective biosynthesis and processing of the CFTR protein (Fanen P et al. J. Biol. Chem., 1997 Nov;272:30563-6). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002496299	SCV002807328	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-04-18	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000007582	SCV003808075	pathogenic	Cystic fibrosis	2022-10-31	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM2 supporting, PM3 very strong, PP3 supporting
Neuberg Centre For Genomic Medicine, NCGM	RCV000007582	SCV004101508	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing	The c.3196C>T (p.Arg1066Cys) in the CFTR gene has been reported in homozygous state in individuals affected with cystic fibrosis (Alonso MJ. et al., 2007). Experimental studies have shown that this missense change severely disrupts CFTR protein processing and biosynthesis in vitro (Van Goor F. et al., 2014). This variant is reported with the allele frequency (0.003%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as a Pathogenic variant. The amino acid Arginine at position 1066 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003473029	SCV004213325	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000723839	SCV004221685	pathogenic	not provided	2022-08-07	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported as compound heterozygous and homozygous in individuals with classic CF (PMIDs: 32539862 (2020), 9475107 (1998), 9375855 (1997), 1379210 (1992)). Additionally, several functional studies indicated this variant causes defective CFTR protein processing and abnormal chloride channel function (PMIDs: 23891399 (2014), 15480987 (2004), 9374552 (1997), 8702904 (1996)). Based on the available information, this variant is classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000723839	SCV005197466	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000007582	SCV000027783	pathogenic	Cystic fibrosis	1992-06-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000723839	SCV001743706	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000723839	SCV001959091	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000723839	SCV001968827	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831541	SCV002083610	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing