ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2052del (p.Lys684fs) (rs121908746)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
American College of Medical Genetics and Genomics (ACMG) RCV000043563 SCV000071399 pathogenic Cystic fibrosis 2004-03-03 practice guideline curation Converted during submission to Pathogenic.
CFTR2 RCV000043563 SCV000071472 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Integrated Genetics/Laboratory Corporation of America RCV000043563 SCV000696884 pathogenic Cystic fibrosis 2016-01-25 criteria provided, single submitter clinical testing Variant summary: This c.2052delA variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 684 and leads to a premature termination codon 38 amino acids downstream. It is predicted to cause a truncated or absent CFTR protein. Loss-of-function due to mutations in this gene is an established disease mechanism in CF or CFTR-RD. This variant was found in 7/119584 chromosomes from broad and large populations of ExAC at a frequency of 0.0000585, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0129603) in this gene. This variant is widely reported as a common CF-causing variant in literature and databases. The variant has been found in patients with classic CF. Multiple clinical labs/reputable databases call this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic.
GeneDx RCV000598782 SCV000709944 pathogenic not provided 2017-07-31 criteria provided, single submitter clinical testing The c.2052delA pathogenic variant in the CFTR gene has been reported previously, sometimes using alternate nomenclature (2184delA), either in the homozygous state or in trans with another CFTR variant in multiple individuals with cystic fibrosis (Lissens et al., 1993; Dork et al., 1994; Jung et al., 2011). The c.2052delA variant causes a frameshift starting with codon Lysine 684, changes this amino acid to an Asparagine residue, and creates a premature Stop codon at position 38 of the new reading frame, denoted p.Lys684AsnfsX38. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2052delA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.2052delA as a pathogenic variant.
Mendelics RCV000043563 SCV001137481 pathogenic Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000726 SCV001157771 pathogenic not specified 2018-08-09 criteria provided, single submitter clinical testing The CFTR c.2052delA; p.Lys684fs variant (rs121908746), also known as 2184delA, is reported in the literature in a homozygous or compound heterozygous state in multiple individuals affected with the pancreatic insufficient form of cystic fibrosis (Chevalier-Porst 1994, Dork 1994, Jung 2011, Lissens 1993, McKone 2003, Ooi 2012, Sosnay 2013, Watson 2004). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 38493), and is found in the non-Finnish European population with an overall allele frequency of 0.01% (15/124874 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be severely pathogenic. References: Chevalier-Porst F et al. Mutation analysis in 600 French cystic fibrosis patients. J Med Genet. 1994 31(7):541-4. Dork T et al. Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients. Hum Genet. 1994 Nov;94(5):533-42. Jung H et al. Heterogeneous spectrum of CFTR gene mutations in Korean patients with cystic fibrosis. Korean J Lab Med. 2011 Jul;31(3):219-24. Lissens W et al. Mild pulmonary, but severe hepatic disease in a cystic fibrosis patient homozygous for a frameshift mutation in the regulatory domain of the CFTR. J Med Genet. 1993 May;30(5):446. McKone EF et al. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 2003 May 17;361(9370):1671-6. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. 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. Watson MS et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med. 2004 Sep-Oct;6(5):387-91.
Baylor Genetics RCV001004282 SCV001163158 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000043563 SCV001169487 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Myriad Women's Health, Inc. RCV000043563 SCV001193952 pathogenic Cystic fibrosis 2019-11-20 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.2052delA(K684Nfs*38, aka 2184delA) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of this disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.2052delA(K684Nfs*38, aka 2184delA) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Johns Hopkins Genomics,Johns Hopkins University RCV000043563 SCV001425386 pathogenic Cystic fibrosis 2020-02-17 criteria provided, single submitter clinical testing Disease-causing CFTR variant. See for phenotype information.

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