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 not specified 2019-06-28 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.
Integrated Genetics/Laboratory Corporation of America RCV000046823 SCV000696958 likely pathogenic Cystic fibrosis 2016-12-01 criteria provided, single submitter clinical testing Variant summary: The CFTR c.3205G>A (p.Gly1069Arg) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 28/120340 control chromosomes at a frequency of 0.0002327, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0062697). Compound heterozygotes of this variant and a CF pathogenic variant were found in at least 4 patients with chronic pancreatitis and in 2 patients with pancreatic insufficient CF. One of the reported CP patients with the variant of interest also carried a likely deleterious variant in SPINK1 (N34S) (Masson_PloS One_2013). Additionally, a CF patient reportedly carried the G1069R variant in cis with a truncating variant L88X, this patient was homozygote for both of the variants (Savov_HMG_1995). These co-occurrences with likely pathogenic variants argue against the pathogenicity of the variant of interest. However, in vitro/vivo functional study indicated that the protein with this variant is retained in ER and has lower open probability and a significant reduction in mean burst duration (Seibert_JBC_1996). Another functional study showed protein with this variant failed to prevent a F508 effect on interburst interval (Dong_PNAS_2012), indicating G1069R probably affects the normal function of CFTR protein. CFTR2 lists variant in 10 CF patients with a classification of mutation with varying consequences. Take all together, the variant shows evidences for pathogenicity however more information is necessary to classify it as true pathogenic, therefore it is classified as likely 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 2019-09-09 criteria provided, single submitter clinical testing Deficient protein function by in vitro/ex vivo assay;Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
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 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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