Submissions for variant NM_000492.4(CFTR):c.1055G>A (p.Arg352Gln)

gnomAD frequency: 0.00002  dbSNP: rs121908753

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007619	SCV000071522	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
PharmGKB	RCV000660773	SCV000783012	drug response	ivacaftor response - Efficacy	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Mendelics	RCV000007619	SCV000886259	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763568	SCV000894407	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2018-10-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985669	SCV001134107	pathogenic	not provided	2019-04-13	criteria provided, single submitter	clinical testing	The variant was found in a symptomatic patient. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. The variant occurs with multiple lone recessive pathogenic variants in the same gene. Functional studies have shown that this variant has a deleterious effect on protein function.
Baylor Genetics	RCV001004254	SCV001163130	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007619	SCV001169460	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000007619	SCV001193913	pathogenic	Cystic fibrosis	2019-11-12	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1055G>A(R352Q) is classified as pathogenic in the context of cystic fibrosis and is associated with the non-classic form of disease. Sources cited for classification include the following: PMID 18456578 and 23974870. Classification of NM_000492.3(CFTR):c.1055G>A(R352Q) 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.‚Äã
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007619	SCV001360485	pathogenic	Cystic fibrosis	2019-10-07	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1055G>A (p.Arg352Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251124 control chromosomes (gnomAD). c.1055G>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Dupuis_2015, Shackelton_1994, 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, and demonstrated that the variant leads to defective chloride channel function (Sosnay 2013). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000007619	SCV001371785	pathogenic	Cystic fibrosis	2020-01-06	criteria provided, single submitter	clinical testing	Previously reported disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Invitae	RCV000007619	SCV001579707	pathogenic	Cystic fibrosis	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 352 of the CFTR protein (p.Arg352Gln). This variant is present in population databases (rs121908753, gnomAD 0.01%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 7544319, 20522854, 27086061, 28646244). ClinVar contains an entry for this variant (Variation ID: 7198). 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%. For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000985669	SCV002051732	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing	PS3, PM3_Supporting, PP3, PM1, PM2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000007619	SCV002507342	pathogenic	Cystic fibrosis	2019-08-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007619	SCV002710182	pathogenic	Cystic fibrosis	2023-05-10	criteria provided, single submitter	clinical testing	The p.R352Q pathogenic mutation (also known as c.1055G>A), located in coding exon 8 of the CFTR gene, results from a G to A substitution at nucleotide position 1055. The arginine at codon 352 is replaced by glutamine, an amino acid with highly similar properties. This mutation was first reported in an individual with pancreatic sufficient cystic fibrosis (CF) and an unknown variant on the other chromosome (Cremonesi L et al. Hum. Mutat., 1992;1:314-9). In two additional studies, p.R352Q was reported in conjunction with p.F508del in an individual with CF and an individual with idiopathic chronic pancreatitis (Zitkiewicz E et al. PLoS ONE, 2014 Mar;9:e89094; Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). This mutation is associated with pancreatic sufficiency and elevated sweat chloride levels (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In a functional study using a Xenopus laevis oocyte model, alterations affecting the positive charge at codon 352 (p.R352A, p.R352E, p.R352Q) were observed to alter pore structure by disrupting the interaction between R352 and D993 (Cui G et al. J. Membr. Biol., 2008 Mar;222:91-106). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000985669	SCV003800364	pathogenic	not provided	2022-08-16	criteria provided, single submitter	clinical testing	The CFTR c.1055G>A; p.Arg352Gln variant (rs121908753) is reported in the literature in several individuals affected with cystic fibrosis (Masson 2013, Ooi 2012, Sosnay 2013). This variant is also reported in ClinVar (Variation ID: 7198), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 352 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.804). Additionally, functional assays demonstrate reduced protein function (Van Goor 2014). Based on available information, this variant is considered to be pathogenic. References Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 Aug 8;8(8):e73522. PMID: 23951356. Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;11(5):355-62. PMID: 22658665. 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. 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 Jan;13(1):29-36. PMID: 23891399.
Neuberg Centre For Genomic Medicine, NCGM	RCV000007619	SCV004047545	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing	The missense variant c.1055G>A p.Arg352Gln in the CFTR gene has been reported in homozygous and compound heterozygous state in individuals affected with cystic fibrosis Sosnay PR, et al., 2013, Nowak JK, et al., 2017. Experimental evidence suggests this variant results in reduced protein function Van Goor F, et al., 2014. This p.Arg352Gln variant is reported with the allele frequency 0.002% in the gnomAD and is novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. The amino acid change p.Arg352Gln in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted to be damaging by SIFT.The amino acid Arginine at position 352 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003473041	SCV004213317	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-11	criteria provided, single submitter	clinical testing
OMIM	RCV000007619	SCV000027820	pathogenic	Cystic fibrosis	1993-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001826444	SCV002078188	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001826444	SCV002507426	pathogenic	CFTR-related disorder	2019-08-14	no assertion criteria provided	clinical testing