ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3205G>A (p.Gly1069Arg) (rs200321110)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046823 SCV000074836 uncertain significance Cystic fibrosis 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1069 of the CFTR protein (p.Gly1069Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs200321110, ExAC 0.08%). This variant has been reported in individuals with cystic fibrosis or congenital bilateral absence of the vas deferens, but either a second variant in CFTR was not discovered in these individuals (PMID: 23974870, 17329263, 9239681, 25910067) or an alternative cause of disease was found (PMID: 8528204). It has also been reported in individuals with chronic pancreatitis (PMID: 23951356, 25033378, 17003641, 11729110, 25869325, 20460946). ClinVar contains an entry for this variant (Variation ID: 53684). Experimental studies have shown that this missense change does not alter CFTR protein expression or maturation, but does have a mild effect on channel kinetics in cell culture, possibly due to the disruption of an intramolecular protein interaction (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, but this prediction has not been confirmed by published transcriptional studies. 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 RCV001000032 SCV000603016 pathogenic none provided 2020-07-27 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 (SIFT, PolyPhen-2) predict that this variant is tolerated. 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. Guan WJ et al. Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis. 2018 May;10(5):2618-2630. Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. 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. 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. 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. 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. 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. 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001375487 SCV000696958 uncertain significance not specified 2021-04-02 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. This frequency is not significantly higher than expected 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, CBAVD, and classical CF, but without identification of a second CFTR mutation (e.g. Chang_2007, Faucz_2007, Giefer_2017, Lucarelli_2015, Ooi_2015, Sofia_2016, Soltysova_2017, Sosnay_2013, Petrova_2019, Luo_2021), 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; e.g. 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). Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories cited the variant with conflicting assessments (Pathogenic/ Likely Pathogenic, n=6; Uncertain Significance, n=4). 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, until additional information becomes available, the variant was classified as VUS-possibly pathogenic.
Counsyl RCV000046823 SCV000795750 uncertain significance Cystic fibrosis 2017-11-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004300 SCV001163176 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009473 SCV001169568 pathogenic CFTR-related disorders 2015-07-03 criteria provided, single submitter curation
Ambry Genetics RCV001019210 SCV001180539 likely pathogenic Inborn genetic diseases 2020-03-19 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). Based on data from ExAC, the A allele has an overall frequency of approximately 0.024% (25/104944). 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 Clinical Services Laboratory,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.
Natera, Inc. RCV001009473 SCV001190640 likely pathogenic CFTR-related disorders 2019-05-20 no assertion criteria provided clinical testing

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