Submissions for variant NM_000492.4(CFTR):c.3485G>A (p.Arg1162Gln)

dbSNP: rs1800120

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671007	SCV000795942	uncertain significance	Cystic fibrosis	2017-12-04	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000732689	SCV000860669	uncertain significance	not provided	2018-04-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000732689	SCV000888086	uncertain significance	not provided	2020-01-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000671007	SCV002027505	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265847	SCV002548060	uncertain significance	not specified	2025-02-17	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3485G>A (p.Arg1162Gln) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 250616 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (8.8e-05 vs 0.013), allowing no conclusion about variant significance. c.3485G>A has been reported in the literature in individuals affected with Cystic Fibrosis and pancreatitis, without strong evidence for causality (example: Strandvik_2001, Monaghan_2000, Atag_2019, Benjar_2020, Benjar_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (e.g. Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 30938940, 32292813, 32026723, 38388235, 10982968, 11788090). ClinVar contains an entry for this variant (Variation ID: 555228). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV000671007	SCV002617621	uncertain significance	Cystic fibrosis	2023-02-10	criteria provided, single submitter	clinical testing	The p.R1162Q variant (also known as c.3485G>A), located in coding exon 22 of the CFTR gene, results from a G to A substitution at nucleotide position 3485. The arginine at codon 1162 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in one individual with frequent pneumonia who had normal pancreatic function and sweat chloride levels; this individual did not have a second CFTR alteration (Strandvik B et al. Genet. Test., 2001;5:235-42). R1162 is located at the hinge region of the CFTR protein and may also act as an anchor (LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376). However, functional studies of a different variant at the same position (p.R1162L) demonstrated normal CFTR protein processing and chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). This amino acid position is highly conserved in available vertebrate species. In addition, p.R1162Q is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002507173	SCV002815698	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-02-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671007	SCV003796652	uncertain significance	Cystic fibrosis	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1162 of the CFTR protein (p.Arg1162Gln). This variant is present in population databases (rs1800120, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis and/or cystic fibrosis (PMID: 11788090, 30938940, 32026723). ClinVar contains an entry for this variant (Variation ID: 555228). 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 expected to disrupt CFTR protein function. 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.
Revvity Omics, Revvity	RCV000732689	SCV003831636	uncertain significance	not provided	2022-07-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000732689	SCV004039790	uncertain significance	not provided	2023-03-27	criteria provided, single submitter	clinical testing	Observed in individuals with features of cystic fibrosis who also harbored second CFTR variants, but familial segregation and additional clinical information was not provided (Banjar et al., 2020); Observed in an individual with alcohol-related pancreatitis and an individual with frequent pneumonias, pancreatic sufficiency, and a normal sweat chloride test (Monaghan et al., 2000; Strandvik et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 23974870, 25033378, 32292813, 34996830, 30938940, 10982968, 32026723, 11788090)
Johns Hopkins Genomics, Johns Hopkins University	RCV000671007	SCV004239076	uncertain significance	Cystic fibrosis	2023-09-13	criteria provided, single submitter	clinical testing	CFTR c.3485G>A has been identified as a single heterozygous variant in two individuals with features of cystic fibrosis, but not a classic cystic fibrosis phenotype. This CFTR variant (rs1800120) is rare (<0.1%) in a large population dataset (gnomADv2.1.1: 25/282012 total alleles; 0.009%; no homozygotes) and has been reported in ClinVar (Variation ID: 555228). Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the second predicts that it would be tolerated. The arginine residue at this position is evolutionarily conserved across all species assessed. We consider the clinical significance of CFTR c.3485G>A to be uncertain at this time.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000732689	SCV005877988	uncertain significance	not provided	2024-03-29	criteria provided, single submitter	clinical testing	The CFTR c.3485G>A; p.Arg1162Gln variant (rs1800120) is reported in the literature in individuals with cystic fibrosis and pancreatitis (Atag 2019, Banjar 2020, Monaghan 2000) and at least one individual with atypical cystic fibrosis (Strandvik 2001). This variant is reported in ClinVar (Variation ID: 555228), and is found in the general population with an overall allele frequency of 0.0089% (25/282012 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.812). Additionally, another variant at this codon (c.3485G>T, p.Arg1162Leu) has been reported in individuals with CFTR-related disorders, such as bronchiectasis and chronic pancreatitis, and is considered mildly pathogenic (Casals 2004, Groman 2002, Lazaro 1999, Ziedalski 2006). However, given the limited clinical data and lack of functional data, the significance of this variant is uncertain at this time. References: Atag E et al. Novel mutations and deletions in cystic fibrosis in a tertiary cystic fibrosis center in Istanbul. Pediatr Pulmonol. 2019 Jun;54(6):743-750. PMID: 30938940. Banjar HH et al. Genotype patterns for mutations of the cystic fibrosis transmembrane conductance regulator gene: a retrospective descriptive study from Saudi Arabia. Ann Saudi Med. 2020 Jan-Feb;40(1):15-24. PMID: 32026723. Casals T et al. Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis? Pancreas. 2004; 28(4):374-9. PMID: 15097853. Groman J et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002; 347(6):401-7. PMID: 12167682. Lazaro C et al. Missense mutations in the cystic fibrosis gene in adult patients with asthma. Hum Mutat. 1999; 14(6):510-9. PMID: 10571949. Monaghan KG et al. Mutation analysis of the cystic fibrosis and cationic trypsinogen genes in patients with alcohol-related pancreatitis. Am J Med Genet. 2000 Sep 11;94(2):120-4. PMID: 10982968. Strandvik B et al. Spectrum of mutations in the CFTR gene of patients with classical and atypical forms of cystic fibrosis from southwestern Sweden: identification of 12 novel mutations. Genet Test. 2001 Fall;5(3):235-42. PMID: 11788090. Ziedalski T et al. Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. Chest. 2006; 130(4):995-1002. PMID: 17035430.
PreventionGenetics, part of Exact Sciences	RCV004735739	SCV005362721	uncertain significance	CFTR-related disorder	2024-07-08	no assertion criteria provided	clinical testing	The CFTR c.3485G>A variant is predicted to result in the amino acid substitution p.Arg1162Gln. This variant has been reported in the compound heterozygous state in an individual with cystic fibrosis (Banjar et al. 2020. PubMed ID: 32026723). This variant has also been reported in the heterozygous state in an individual with cystic fibrosis, an individual with frequent pneumonias who had normal pancreatic function and sweat chloride levels, and in an individual with pancreatitis however, the presence of a second CFTR variant was either unknown or not specified in any of these individuals (Monaghan et al. 2000. PubMed ID: 10982968; Strandvik et al. 2001. PubMed ID: 11788090; Atag et al. 2019. PubMed ID: 30938940). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.