ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2421A>G (p.Ile807Met) (rs1800103)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197986 SCV000254590 benign Cystic fibrosis 2020-12-04 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725433 SCV000336902 uncertain significance not provided 2017-11-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515401 SCV000611383 uncertain significance Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000313144 SCV000696899 likely benign not specified 2020-12-28 criteria provided, single submitter clinical testing Variant summary: CFTR c.2421A>G (p.Ile807Met) results in a conservative amino acid change located in the CFTR regulator domain (IPR025837) of 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 0.00078 in 182610 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk (0.00078 vs 0.0063), allowing no conclusion about variant significance. c.2421A>G, has been reported in the literature in individuals affected with Idiopathic Chronic Pancreatitis (ICP) (Masson_2013) and healthy controls with comparable allele frequencies (LaRusch_2014). Multiple ICP patients reported with this variant also carried another disease variant in either CFTR or the CPANC causative gene SPINK1 (Masson_2013, Pelletier _2010, and Schneider_2011), indicating that the contribution of this particular variant to the etiology of pancreatitis is unlikely. In addition, multiple studies list this variant as neutral variant with no clinical consequence. (Fanen_2014, Castellani_2008). In toto, these data do not allow any conclusion about variant significance in the context of CF, CFTR-RD or chronic pancreatitis. At least two independent publications reporting experimental evidence evaluating an impact on protein function were ascertained in the context of this evaluation. These results showed no damaging effect of this variant on CFTR maturation as well as chloride conductance (example, Vankeerberghen_1998, Raraigh_2018). Seven clinical diagnostic laboratories and one database (CFTR-France) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments ranging from benign (n=2), likely benign (n=1), VUS (n=4). CFTR-France database reports a pathogenic classification for a phenotype of CFTR-related disorders due to a report of its occurrence as a complex variant (I807M;Q1352H (Q1352H classified as VUS-possibly pathogenic in our internal database)) in three patients with Congenital bilateral absence of vas deferens (CBAVD) who carried p.F508del on the other allele and in one asymptomatic compound heterozygote (ASCH) (with p.F508del), for a total of 4 individuals without ascertained familial segregation (Claustres_2017). However, these findings cannot be translated into evidence supporting the pathogenicity of this variant in isolation. Several submitters also cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282082 SCV000883597 uncertain significance none provided 2020-01-31 criteria provided, single submitter clinical testing The CFTR c.2421A>G, p.Ile807Met variant (rs1800103), is reported in the literature in the compound heterozygous state or in the heterozygous state with an unknown second allele in individuals affected with chronic pancreatitis (Danziger 2004, Keiles 2006, Masson 2013), cystic fibrosis (Behar 2017, Kolesar 2008, Schrijver 2016), and congenital bilateral absence of vas deferens (Vankeerberghen 1998). However, this variant has also been observed in equal numbers of control samples (LaRusch 2014, Makrythanasis 2010, Tzetis 2007). The variant is reported in ClinVar (Variation ID: 35842), and is found in the South Asian population with an overall allele frequency of 0.52% (77/14800 alleles, including a single homozygote) in the Genome Aggregation Database. The isoleucine at codon 807 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, functional studies show no defects in protein maturation or chloride channel activity (Raraigh 2018, Vankeerberghen 1998). Due to conflicting information, the clinical significance of the p.Ile807Met variant is uncertain at this time. References: Behar DM et al. Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening. Mol Genet Genomic Med. 2017 Feb 19;5(3):223-236. Danziger KL et al. Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis. Hum Reprod. 2004 Mar;19(3):540-6. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. Kolesar P et al. Mutation analysis of the CFTR gene in Slovak cystic fibrosis patients by DHPLC and subsequent sequencing: identification of four novel mutations. Gen Physiol Biophys. 2008 Dec;27(4):299-305. 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. Makrythanasis P et al. Cystic fibrosis conductance regulator, tumor necrosis factor, interferon alpha-10, interferon alpha-17, and interferon gamma genotyping as potential risk markers in pulmonary sarcoidosis pathogenesis in Greek patients. Genet Test Mol Biomarkers. 2010 Aug;14(4):577-84. 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. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Schrijver I et al. The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. J Mol Diagn. 2016 Jan;18(1):39-50. Tzetis M et al. Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis. Clin Genet. 2007 May;71(5):451-7. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 Oct;7(11):1761-9.
Johns Hopkins Genomics, Johns Hopkins University RCV000197986 SCV000992327 benign Cystic fibrosis 2019-09-24 criteria provided, single submitter clinical testing
CFTR-France RCV001009483 SCV001169578 pathogenic CFTR-related disorders 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001015492 SCV001176331 uncertain significance Inborn genetic diseases 2020-03-17 criteria provided, single submitter clinical testing The p.I807M variant (also known as c.2421A>G), located in coding exon 14 of the CFTR gene, results from an A to G substitution at nucleotide position 2421. The isoleucine at codon 807 is replaced by methionine, an amino acid with highly similar properties. This variant was found to co-occur with a pathogenic mutation in CFTR and SPINK1 in an individual presenting with chronic pancreatitis (Schneider A et al. Gastroenterology, 2011 Jan;140:162-71). In a cohort of 253 French individuals with idiopathic chronic pancreatitis, two were identified as heterozygous for p.I807M; one was also heterozygous for p.R117H, phase uncertain (Masson E et al. PLoS ONE, 2013 Aug;8:e73522). Another study observed this variant in individuals with pancreatitis and healthy controls at the same frequency (LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376). Functional data demonstrated this variant displayed both maturation of the protein and chloride channel activity similar to that of wild-type protein (Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9; Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077), although bicarbonate permeability and conductance, which are more relevant in the development of pancreatitis, were not assessed. Based on data from gnomAD, the G allele has an overall frequency of approximately 0.07% (148/210958) total alleles studied. The highest observed frequency was 0.52% (77/14800) of South Asian alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV001009483 SCV001320417 likely benign CFTR-related disorders 2017-04-27 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000725433 SCV001714845 uncertain significance not provided 2019-08-13 criteria provided, single submitter clinical testing
Pars Genome Lab RCV000197986 SCV001736835 uncertain significance Cystic fibrosis 2021-05-18 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000197986 SCV001822107 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
GeneDx RCV000725433 SCV001822358 likely benign not provided 2018-06-27 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 29805046, 9736778, 24631642, 28194692, 20460946, 26708955, 17489851, 14998948, 17003641, 20977904, 19202204, 19812525, 25033378, 20722470, 23951356)
Natera, Inc. RCV000197986 SCV001455989 likely benign Cystic fibrosis 2019-08-05 no assertion criteria provided clinical testing

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