ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3485G>T (p.Arg1162Leu) (rs1800120)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000248703 SCV000304490 likely benign not specified criteria provided, single submitter clinical testing
Invitae RCV000462037 SCV000562305 benign Cystic fibrosis 2020-11-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726998 SCV000704812 uncertain significance not provided 2018-08-30 criteria provided, single submitter clinical testing
Counsyl RCV000462037 SCV000795466 likely benign Cystic fibrosis 2017-11-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282937 SCV000883574 pathogenic none provided 2020-08-13 criteria provided, single submitter clinical testing The CFTR c.3485G>T, p.Arg1162Leu variant (rs1800120) has not been associated with classic cystic fibrosis (Fanen 1992, Narzi 2007, Salinas 2016, Sosnay 2013, see link to CFTR database), but has been found in individuals with CFTR-related disorders, such as bronchiectasis and chronic pancreatitis (Casals 2004, Groman 2002, Lazaro 1999, Ziedalski 2006). This variant has also been identified in 15 individuals with CFTR-related disorders, including 5 individuals who carry another pathogenic variant. The p.Arg1162Leu variant is listed in ClinVar (Variation ID: 256253), and is found in the non-Finnish European population with an allele frequency of 0.13% (164/126,100 alleles) in the Genome Aggregation Database. The variant is slightly enriched in pancreatitis patients tested by ARUP Laboratories compared to the general population (Genome Aggregation Database), with an odds ratio of 2.2 (95 percent CI: 1.3 to 3.7, adjusted p-value: 0.04). The arginine at position 1162 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Although the p.Arg1162Leu variant is not expected to cause classical cystic fibrosis, when paired with a second pathogenic CFTR variant on the opposite chromosome, the p.Arg1162Leu variant may contribute to CFTR-related disorders, such as pancreatitis. References: Link to CFTR database: Casals T et al. Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis? Pancreas. 2004; 28(4):374-9. Fanen P et al. Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions. Genomics. 1992; 13(3):770-6. Groman J et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002; 347(6):401-7. Lazaro C et al. Missense mutations in the cystic fibrosis gene in adult patients with asthma. Hum Mutat. 1999; 14(6):510-9. Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007; 72(1):39-46. Salinas D et al. Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California. PLoS One. 2016; 11(5):e0155624. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000726998 SCV001155243 likely pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
CFTR-France RCV001009501 SCV001169596 pathogenic CFTR-related disorders 2018-03-26 criteria provided, single submitter curation
Ambry Genetics RCV001020415 SCV001181892 uncertain significance Inborn genetic diseases 2020-01-21 criteria provided, single submitter clinical testing The p.R1162L variant (also known as c.3485G>T), located in coding exon 22 of the CFTR gene, results from a G to T substitution at nucleotide position 3485. The arginine at codon 1162 is replaced by leucine, an amino acid with dissimilar properties. This variant has been observed with a pathogenic mutation and other CFTR alterations in individuals described with atypical cystic fibrosis, and reportedly asymptomatic individuals, but specific clinical information was limited (Groman JD et al. N Engl J Med. 2002;347(6):401-407; Claustres M et al. Hum Mutat. 2017;38(10):1297-1315). This variant has been detected in both pancreatitis patients and controls in CFTR pancreatitis association studies (Casals T et al. Pancreas. 2004;28(4):374-379; Tzetis M et al Clin Genet. 2007; 71(5):451-457; Cohn JA et al. Hum Mutat. 2005; 26(4):303-307; Giefer MJ et al. J Pediatr. 2017;186:95-100). Functional studies found this alteration resulted in conductance of chloride similar to wild type; in addition, this alteration was identified in trans with a pathogenic mutation two times in fathers of children with cystic fibrosis (<span style="background-color:initial">Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). In another study, transfected cells exhibited protein processing and expression at near normal levels compared to wild type (Salinas DB et al. J. Cyst. Fibros., 2015 Nov;14:714-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. <span style="background-color:initial">Based on available evidence, this variant is unlikely to be causative of classic CF; however, its clinical contribution to the development of a CFTR-related disorder is uncertain.
Illumina Clinical Services Laboratory,Illumina RCV001009501 SCV001325860 uncertain significance 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). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000248703 SCV001482132 benign not specified 2021-02-05 criteria provided, single submitter clinical testing Variant summary: CFTR c.3485G>T (p.Arg1162Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00071 in 253674 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00071 vs 0.013), allowing no conclusion about variant significance. c.3485G>T has been widely reported in the literature in asymptomatic compound heterozygotes with non-informative genotypes such as another benign/non-CF causing variant or another reported pathogenic CF-causing variant, as a sole variant in a non-informative genotype in settings of CFTR-RD, and in settings of indeterminate newborn screening (example, Claustres_2017, Minso_2020, Sosnay_2013). The fact that this variant was reported among 6 non-affected fathers harboring this variant with another CFTR-causing variant in trans supports the lack of association or non-penetrance of this variant within settings of infertility (Sosnay_2013). Additionally, numerous studies spanning over a decade (1992-2010) predating the ones cited above cite the variant as a polymorphism. These data do not allow any conclusion about variant significance. Practice guidelines aimed at developing international consensus have listed this variant among non-CF causing variation while not including this among CFTR variants with varying or indeterminate clinical consequences (Girardet_2015). This is further supported by the conclusions reported in prominent databases such as CFTR2, which report this variant as having no clinical consequence in the settings of CF. To our knowledge, no conclusive experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments ranging from Pathogenic to VUS and Benign, some of whom cite overlapping evidence utilized in the context of this evaluation. Based on the lack of firm/conclusive evidence supporting an actionable outcome following a cross-sectional review of literature spanning over 3 decades as outlined above, the variant was classified as benign in the context of Cystic Fibrosis and its associated phenotypes.
Institute of Reproductive Genetics, University of Münster RCV001640482 SCV001860334 likely pathogenic Obstructive azoospermia 2021-08-23 criteria provided, single submitter clinical testing

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