Submissions for variant NM_000492.4(CFTR):c.1040G>C (p.Arg347Pro)

dbSNP: rs77932196

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
American College of Medical Genetics and Genomics (ACMG)	RCV000007530	SCV000071389	pathogenic	Cystic fibrosis	2004-03-03	practice guideline	curation	Converted during submission to Pathogenic.
CFTR2	RCV000007530	SCV000071521	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001530124	SCV000603032	pathogenic	not provided	2021-12-06	criteria provided, single submitter	clinical testing	The CFTR c.1040G>C; p.Arg347Pro variant (rs77932196) has been reported in multiple patients diagnosed with cystic fibrosis (Chavez-Saldana 2010, Dean 1990, Ivady 2011) and is associated with both pancreatic-sufficient and -insufficient disease (Dean 1990, Ooi 2012, CFTR2 database). It has also been identified in individuals with congenital bilateral absence of vas deferens and infertility (Amato 2012, Tomaiuolo 2011) when found in-trans with a mildly pathogenic CFTR variant (Tomaiuolo 2011). Functional characterization of the p.Arg347Pro variant protein indicates a failure to generate mature protein, leading to the loss of chloride transport activity (Sosnay 2013, Van Goor 2014). The variant is listed as pathogenic in ClinVar (Variation ID: 7110) and is observed twice in the Exome Variant Server (2/13006 alleles) and 6 times in the Genome Aggregation Database (6/245866 alleles). The arginine at residue 347 is highly conserved (Alamut v2.10), and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that this variant is deleterious. Based on the above information, p.Arg347Pro variant is classified as moderately pathogenic. References: CFTR2 database: https://www.cftr2.org/ Amato F et al. Extensive molecular analysis of patients bearing CFTR-related disorders. J Mol Diagn. 2012; 14(1):81-9. Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010; 62(6):546-52. Dean M et al. Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients. Cell. 1990; 61(5):863-70. Ivady G et al. Distribution of CFTR mutations in Eastern Hungarians: relevance to genetic testing and to the introduction of newborn screening for cystic fibrosis. J Cyst Fibros. 2011; 10(3):217-20. 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. Tomaiuolo R et al. Enhanced frequency of CFTR gene variants in couples who are candidates for assisted reproductive technology treatment. Clin Chem Lab Med. 2011; 49(8):1289-93. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007530	SCV000696817	pathogenic	Cystic fibrosis	2017-01-27	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.1040G>C (p.Arg347Pro) variant located in the ABC transporter type 1, transmembrane domain (via InterPro) involves the alteration of a conserved nucleotide, which 4/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121338, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant of 1/77. Multiple publications have cited the variant in affected individuals, and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest is a known, well-established common Pathogenic. Therefore, the variant of interest has been classified as "pathogenic."
Mendelics	RCV000007530	SCV000886258	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004251	SCV001163127	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007530	SCV001169458	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000007530	SCV001194235	pathogenic	Cystic fibrosis	2019-12-20	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1040G>C(R347P) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 12454843, 23974870, 8535440 and 20448091. Classification of NM_000492.3(CFTR):c.1040G>C(R347P) 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000007530	SCV001425443	pathogenic	Cystic fibrosis	2020-02-27	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Invitae	RCV000007530	SCV001588862	pathogenic	Cystic fibrosis	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 347 of the CFTR protein (p.Arg347Pro). This variant is present in population databases (rs77932196, gnomAD 0.005%). This missense change has been observed in individual(s) with cystic fibrosis and congenital absence of the vas deferns (PMID: 1723032, 2344617, 10376575, 12400067, 31523618). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7110). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 23891399, 23974870). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001530124	SCV002046175	pathogenic	not provided	2021-01-18	criteria provided, single submitter	clinical testing	This variant has been reported in individuals affected with Cystic Fibrosis in the published literature (PMID: 15371902 (2004), 32429104 (2020), 31523618 (2019), 22658665 (2012), 20448091 (2010)). Functional studies have shown that this variant results in defective CFTR protein maturation and protein conductance (PMID: 24440181 (2014), 23891399 (2014), 23974870 (2013)). Therefore, the variant is classified as pathogenic.
Ambry Genetics	RCV000007530	SCV002699407	pathogenic	Cystic fibrosis	2021-12-27	criteria provided, single submitter	clinical testing	The p.R347P pathogenic mutation (also known as c.1040G>C), located in coding exon 8 of the CFTR gene, results from a G to C substitution at nucleotide position 1040. The arginine at codon 347 is replaced by proline, an amino acid with dissimilar properties. This pathogenic mutation has been associated with variable pancreatic sufficiency, variable pulmonary disease, and elevated sweat chloride levels; in addition, functional in vitro studies showed significantly decreased CFTR expression and no chloride conduction (Braun AT et al. J Cyst Fibros. 2006;5(1):33-41; Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002504761	SCV002799274	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-03-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473002	SCV004213331	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-06	criteria provided, single submitter	clinical testing
OMIM	RCV000007530	SCV000027731	pathogenic	Cystic fibrosis	1991-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000007530	SCV001622786	not provided	Cystic fibrosis		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530124	SCV001744798	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001530124	SCV001956542	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001530124	SCV001971843	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831520	SCV002078183	pathogenic	CFTR-related disorders	2017-03-17	no assertion criteria provided	clinical testing