Submissions for variant NM_000492.4(CFTR):c.2421A>G (p.Ile807Met)

gnomAD frequency: 0.00034  dbSNP: rs1800103

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197986	SCV000254590	benign	Cystic fibrosis	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	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	2024-08-02	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 estimated 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 3 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, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 28603918, 14998948, 24631642, 18716917, 17003641, 19202204, 25033378, 20722470, 23951356, 25651269, 20460946, 29805046, 20977904, 26708955, 17489851, 9736778, 26277102, 19812525, 38388235). ClinVar contains an entry for this variant (Variation ID: 35842). Based on the evidence outlined above, the variant in isolation was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725433	SCV000883597	uncertain significance	not provided	2023-11-09	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 also reported in ClinVar (Variation ID: 35842). This variant 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 predict that this variant is deleterious (REVEL: 0.738). 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. PMID: 28546993. 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. PMID: 14998948. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. 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. PMID: 19202204. 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. 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. PMID: 20722470. 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. 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. PMID: 29805046. 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. PMID: 26708955. 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. PMID: 17489851. 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. PMID: 9736778.
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 disorder	2024-01-24	criteria provided, single submitter	curation
Ambry Genetics	RCV000197986	SCV001176331	uncertain significance	Cystic fibrosis	2024-04-19	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. 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 Laboratory Services, Illumina	RCV001009483	SCV001320417	likely benign	CFTR-related disorder	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
Genome-Nilou 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)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000725433	SCV002047104	likely benign	not provided	2022-11-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257361	SCV002529693	likely benign	Hereditary pancreatitis	2021-05-17	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000725433	SCV004158955	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725433	SCV004235038	uncertain significance	not provided	2023-04-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000197986	SCV001455989	likely benign	Cystic fibrosis	2019-08-05	no assertion criteria provided	clinical testing