ClinVar Miner

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

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Total submissions: 9
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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 2019-12-31 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 RCV000248703 SCV000883574 pathogenic not specified 2018-07-10 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 2015, Sosnay 2013, CFTR2 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). The 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 observed in the general population databases at a frequency of 0.08 percent in the 1000 Genomes Project (4/5008 alleles), 0.06 percent in the Exome Variant Server (8/13004 alleles, 1 homozygote), and 0.07 percent in the Genome Aggregation Database (187/276320 alleles). The variant is slightly enriched in pancreatitis patients tested 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 (Alamut v2.9.0), and computational algorithms (Align GVGD, Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on CFTR protein structure or function. Although the CFTR 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: 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 Conflicting evidence
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.

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