Submissions for variant NM_000492.4(CFTR):c.3209G>A (p.Arg1070Gln) (rs78769542)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV000660859	SCV000783098	drug response	ivacaftor response - Efficacy	2018-03-23	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046825	SCV000052172	likely pathogenic	Cystic fibrosis	2020-07-13	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3209G>A (p.Arg1070Gln) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251348 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.00061 vs 0.013), allowing no conclusion about variant significance. This variant has been reported in several patients with classic CF, non-classic CF, or CBAVD and in several patients it was observed in cis with S466X forming a complex allele (Krasnov_2008, Ivanov_2018). Available patient data suggests that this variant alone is expected to cause mild diseases such as CF/NC and/or CBAVD, while in cis with p.S466X variant, it causes classic CF (Krasnov_2008). Although this variant is able to mature and reach the cell surface and was found to have no significant effect on chloride transport, it was found to cause relatively subtle channel defects with functional consequences of a lower open probability of the channel, lower cyclic AMP-stimulated iodide efflux, and lower bicarbonate transport (Seibert_1996, Krasnov_2008, Sosnay_2013, Choi_2001). In these studies, while maturation assay was performed on HEK-293 and COS cells, channel function and channel transport assays were performed on HEK293 and CHO cells. In FRT cells, however, chloride transport as well as maturation was found to be significantly reduced for this variant (Van Goor_2014). These functional differences might be due to different cell lines being used in different studies and technical backgrounds; however, all these studies suggest for a functional impairment for the variant. Multiple clinical laboratories have classified this variant as likely pathogenic/pathogenic, while CFTR2 database has classified this variant as 'indeterminate' for CF-causation. The variant's presence in cis with a truncating mutation, its association with CF/NC, CBAVD or other CFTR-RDs, and frequency data in South Asian are suggestive of a variable penetrance associated with this variant. A recent publication of policy recommendations towards improvement of the best practice guidelines for preimplantation genetic diagnosis of CF also reports this variant as a 'common variant with varying or indetermined clinical consequences' (Girardet_2015). Additionally, CFTR2 database includes these statements about the variant: "The drug ivacaftor (Kalydeco) has been approved in some countries for individuals with this variant. Because of this [clinical] variability, it is very important that CLINICAL CRITERIA ALONE be used to determine whether a person with this variant has CF. Because the clinical manifestations of CF can vary over the course of a person's lifetime, people who have this variant plus a variant that is known to cause CF should have periodic check-ups with their doctor even if they have no clinical signs or symptoms of CF at the present time." Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl	RCV000046825	SCV000220326	likely pathogenic	Cystic fibrosis	2014-05-18	criteria provided, single submitter	literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000724647	SCV000227629	pathogenic	not provided	2015-04-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000724647	SCV000885179	pathogenic	not provided	2018-04-22	criteria provided, single submitter	clinical testing	The c.3209G>A; p.Arg1070Gln variant (rs78769542) has been observed in the compound heterozygous state in patients diagnosed with cystic fibrosis with pancreatic insufficiency (see link to CFTR2 database), or mild and atypical CFTR-related disorders, such as chronic pancreatitis and congenital absence of vas deferens (Feldmann 2003, Krasnov 2008), but its effects in the homozygous state are unknown. It is reported as pathogenic or likely pathogenic by several laboratories in Clinvar (Variation ID: 35866) and is observed in the South Asian population at an overall frequency of 0.46% (141/ 30766 alleles, 3 homozygotes) in the Genome Aggregation Database. The arginine at codon 1070 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Functional characterization of the variant protein is inconclusive on the expression level of the mature protein (Cotten 1996, Seibert 1996, Sosnay 2013, Van Goor 2014), but indicates an observable decrease in anion transport activity (Choi 2001, Seibert 1996, Sosnay 2013, Van Goor 2014). Based on available information, the p.Arg1070Gln variant is classified as pathogenic, with a variable presentation of clinical phenotypes. References: Link to CFTR2 database: https://www.cftr2.org/ Choi J et al. Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis. Nature. 2001;410(6824):94-7. Cotten J et al. Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator. J Biol Chem. 1996;271(35):21279-84. Feldmann D et al. CFTR genotypes in patients with normal or borderline sweat chloride levels. Hum Mutat. 2003;22(4):340. Krasnov K et al. Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships. Hum Mutat. 2008;29(11):1364-72. Seibert F et al. Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity. J Biol Chem. 1996;271(25):15139-45. 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. 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.
Mendelics	RCV000046825	SCV000886355	uncertain significance	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000724647	SCV000927819	uncertain significance	not provided	2018-07-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004301	SCV001163178	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV001009383	SCV001169236	pathogenic	Cystic fibrosis; CFTR-related disorders	2015-07-03	criteria provided, single submitter	curation	when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Ambry Genetics	RCV001019233	SCV001180564	pathogenic	Inborn genetic diseases	2018-03-30	criteria provided, single submitter	clinical testing	The p.R1070Q pathogenic mutation (also known as c.3209G>A), located in coding exon 20 of the CFTR gene, results from a G to A substitution at nucleotide position 3209. The arginine at codon 1070 is replaced by glutamine, an amino acid with highly similar properties. Functional studies have shown that this mutation does not affect protein processing (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7), but it was observed to decrease the open probability of the channel (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45). This mutation has been reported as a variant of varying clinical consequence (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed March 30, 2018); when in trans with a second disease causing mutation it may result in cystic fibrosis, CFTR-related disorders, or no phenotype (Bombieri C et al. Semin Respir Crit Care Med, 2015 Apr;36:180-93; Girardet A et al. Eur. J. Hum. Genet., 2016 Apr;24:469-78). Of note, this mutation has also been observed as part of a complex allele with p.S466* (Krasnov KV et al. Hum. Mutat., 2008 Nov;29:1364-72; Lucarelli M et al. Mol. Med., 2015 Apr;21:257-75). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Centogene AG - the Rare Disease Company	RCV000046825	SCV001424390	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing
Invitae	RCV000046825	SCV001718362	benign	Cystic fibrosis	2020-11-13	criteria provided, single submitter	clinical testing