Submissions for variant NM_000492.4(CFTR):c.3205G>A (p.Gly1069Arg)

gnomAD frequency: 0.00035  dbSNP: rs200321110

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000046823	SCV000074836	uncertain significance	Cystic fibrosis	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1069 of the CFTR protein (p.Gly1069Arg). This variant is present in population databases (rs200321110, gnomAD 0.1%). This missense change has been observed in individual(s) with cystic fibrosis, congenital bilateral absence of the vas deferens, and chronic pancreatitis (PMID: 8528204, 9239681, 11729110, 17003641, 17329263, 20460946, 23951356, 23974870, 25033378, 25869325, 25910067). ClinVar contains an entry for this variant (Variation ID: 53684). 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 not expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 8662892, 18305154). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Eurofins Ntd Llc (ga)	RCV000506564	SCV000331451	uncertain significance	not provided	2016-04-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506564	SCV000601092	likely pathogenic	not provided	2017-06-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506564	SCV000603016	pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing	The CFTR c.3205G>A; p.Gly1069Arg variant (rs200321110) is reported in the literature in multiple individuals affected with CFTR-related disorders (Keiles 2006, LaRusch 2014, Masson 2013, Ratbi 2007). It has also been reported in patients with cystic fibrosis without an identified second variant in CFTR (Angelicheva 1997, Savov 1994, Sosnay 2013), and was found in-cis with a truncating variant in one patient (Savov 1994). This variant is reported in ClinVar (Variation ID: 53684), and is found in the general population with an overall allele frequency of 0.027% (75/282294 alleles) in the Genome Aggregation Database. The glycine at codon 1069 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.603). However, other computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. In vitro functional analyses demonstrate that this variant does not alter protein expression, but reduces channel function (Seibert 1996). Based on the range of clinical symptoms observed in patients with this variant, we consider the p.Gly1069Arg variant to be pathogenic with varying clinical consequences. References: Angelicheva D et al. Cystic fibrosis mutations and associated haplotypes in Bulgaria - a comparative population genetic study. Hum Genet. 1997 Apr;99(4):513-20. PMID: 9099843. Guan WJ et al. Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis. 2018 May;10(5):2618-2630. PMID: 29997923. Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014 Jul 17;10(7):e1004376. PMID: 25033378. 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. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007 May;22(5):1285-91. PMID: 17329263. Savov A et al. Identification of six novel mutations in the CFTR gene of patients from Bulgaria by screening the twenty seven exons and exon/intron boundaries using DGGE and direct DNA sequencing. Hum Mol Genet. 1994 Jan;3(1):57-60. PMID: 7512860. Seibert FS 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 Jun 21;271(25):15139-45. PMID: 8662892. 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. Zou WB et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. 2018 Nov 12;9(11):204. PMID: 30420730.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375487	SCV000696958	uncertain significance	not specified	2023-09-15	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3205G>A (p.Gly1069Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 251634 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00026 vs 0.013), allowing no conclusion about variant significance. c.3205G>A has been reported in the literature in compound heterozygosity with a second pathogenic CFTR mutation in individuals affected with CF (e.g. DeBoeck_2005, Savov_1995, Mota_2018, Petrova_2019) and chronic pancreatitis (e.g. Keiles_2006, Noone_2001), but also in an infant reported with a positive immunoreactive trypsinogen test upon newborn screening whom did not exhibit other signs or symptoms of CF or CF-related disease upon follow-ups through the age of 3 years (Ooi_2015). The variant has also been reported in multiple individuals affected with these and other CFTR-Related Diseases, including pancreatitis, congenital bilateral absence of the vas deferens , and classical CF, but without a second CFTR mutation identified/specified (e.g. Chang_2007, Faucz_2007, Giefer_2017, Lucarelli_2015, Ooi_2015, Sofia_2016, Soltysova_2017, Sosnay_2013, Petrova_2019, Luo_2021, Raraigh_2022), therefore these data do not allow any definitive conclusions about variant significance. In addition, the variant has been reported in phase with another pathogenic mutation in several affected individuals, including at least 4 occurrences in cis with p.Leu88X in CF patients from Bulgaria and Greece (e.g. Ratbi_2007), and at least 2 occurrences in cis with p.Tyr109Cys in CF patients from Brazil (e.g. Mota_2018), suggesting that the phenotype in these individuals may not be attributable to the p.Gly1069Arg variant. Furthermore, co-occurrence with another pathogenic variant associated with pancreatitis risk has also been reported in an individual affected with chronic pancreatitis (SPINK1, p.Asn34Ser; Masson_2013), therefore the contributions of the individual variants to the phenotype in this patient cannot be determined. Several publications report in vitro experimental evidence suggesting that the variant does not affect protein expression or maturation, but may alter intracellular localization and moderately impair channel function (e.g. Dong_2012, Seiber_1996, Serohijos_2008). The following publications have been ascertained in the context of this evaluation (PMID: 10980579, 17539902, 10923036, 15772171, 22210114, 17718859, 28502372, 29589582, 29997923, 17003641, 25910067, 32777524, 23951356, 30232781, 11729110, 25963003, 31245908, 34782259, 17329263, 8528204, 8662892, 18305154, 27264265, 28544683, 23974870, 32150665). Fourteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifying the variant as pathogenic (n=2)/likely pathogenic (n=6) or VUS (n=6). The CFTR2 database cites this variant as having varying consequences, indicating that some patients with this variant, combined with another CF-causing variant, have CF while others do not, suggesting that clinical information is necessary for diagnosis of disease in individuals found to carry this variant. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until additional information becomes available.
Counsyl	RCV000046823	SCV000795750	uncertain significance	Cystic fibrosis	2017-11-22	criteria provided, single submitter	clinical testing
CFTR-France	RCV001009473	SCV001169568	pathogenic	CFTR-related disorders	2015-07-03	criteria provided, single submitter	curation
Ambry Genetics	RCV000046823	SCV001180539	likely pathogenic	Cystic fibrosis	2023-03-14	criteria provided, single submitter	clinical testing	The p.G1069R variant (also known as c.3205G>A), located in coding exon 20 of the CFTR gene, results from a G to A substitution at nucleotide position 3205. The glycine at codon 1069 is replaced by arginine, an amino acid with dissimilar properties. This variant was first reported in an individual with cystic fibrosis, pancreatic insufficiency, and significant lung disease in cis with a nonsense mutation and in trans with p.F508del (Savov A et al. Hum. Mol. Genet., 1994 Jan;3:57-60). The p.G1069R variant has been reported as a variant of varying clinical consequences (VVCC) and has been identified in trans with a pathogenic mutation in individuals with intermediate sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7; Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98). Two siblings with idiopathic chronic pancreatitis (ICP) were both found to be heterozygous for p.G1069R and a second variant in CFTR; however, phase was not confirmed (Noone PG et al. Gastroenterology, 2001 Dec;121:1310-9). Another study of individuals with ICP identified this variant in an individual who was also heterozygous for the p.N34S mutation in SPINK1 (Masson E et al. PLoS ONE, 2013 Aug;8:e73522). Functional studies demonstrated that while the p.G1069R variant in CFTR does not impact protein maturation or conductance, it does reduce the probability of channel opening (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Illumina Laboratory Services, Illumina	RCV001009473	SCV001325544	uncertain significance	CFTR-related disorders	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Johns Hopkins Genomics, Johns Hopkins University	RCV000046823	SCV001425380	likely pathogenic	Cystic fibrosis	2020-02-10	criteria provided, single submitter	clinical testing	CFTR variant associated with variable clinical consequences. See www.CFTR2.org for phenotype information.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002226453	SCV002505583	uncertain significance	Hereditary pancreatitis	2022-04-05	criteria provided, single submitter	clinical testing	Criteria applied: PM3, PP3 this Variant was identiefied with NM_003122.5 (SPINK1):c.101A>G, p.(Asn34Ser) and the UTR variant c.-4141G>T in patient with hereditary pancreatitis
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000046823	SCV002507382	uncertain significance	Cystic fibrosis	2020-07-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407423	SCV004115124	uncertain significance	CFTR-related condition	2023-12-01	criteria provided, single submitter	clinical testing	The CFTR c.3205G>A variant is predicted to result in the amino acid substitution p.Gly1069Arg. This variant has been reported for a range of phenotypes including pancreatitis, bronchiectasis, sarcoidosis, cystic fibrosis and congenital bilateral absence of the vas deferens (Masson et al 2013. PubMed ID: 23951356; Keiles et al 2006. PubMed ID: 17003641; Ratbi et al 2007. PubMed ID: 17329263; Bombieri et al 2000. PubMed ID: 10980579; Guan et al 2018. PubMed ID: 29997923). Functional studies in cell lines suggest the p.Gly1069Arg variant does not affect CFTR transmembrane conductance (see supplemental table 2 in Sosnay et al 2013. PubMed ID: 23974870; Seibert et al 1996. PubMed ID: 8662892). This variant has conflicting interpretations in ClinVar ranging from uncertain significance to pathogenic by different laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/53684/). This variant is reported in 0.12% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003474569	SCV004213280	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000046823	SCV001163176	likely pathogenic	Cystic fibrosis	2022-02-21	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001009473	SCV001190640	likely pathogenic	CFTR-related disorders	2019-05-20	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001009473	SCV002507469	likely pathogenic	CFTR-related disorders	2020-07-30	no assertion criteria provided	clinical testing