ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3846G>A (p.Trp1282Ter) (rs77010898)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000271658 SCV000603029 pathogenic not provided 2017-10-18 criteria provided, single submitter clinical testing The CFTR c.3846G>A; p.Trp1282Ter variant (rs77010898) has been reported to cause classic cystic fibrosis (CF) when on the opposite chromosome from another severe variant (CFTR2 database, Sosnay 2013). This variant is reported as pathogenic in ClinVar (Variation ID: 7129), and found in the general population with an overall allele frequency of 0.04% (114/276622 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and 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 CFTR2 database: http://cftr2.org/ Sosnay P et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013. 45(10):1160-7
Ambry Genetics RCV000623012 SCV000742085 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
American College of Medical Genetics and Genomics (ACMG) RCV000007549 SCV000071407 pathogenic Cystic fibrosis 2004-03-03 practice guideline curation Converted during submission to Pathogenic.
CFTR2 RCV000007549 SCV000071562 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Counsyl RCV000007549 SCV000485155 pathogenic Cystic fibrosis 2015-11-27 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000271658 SCV000330916 pathogenic not provided 2018-01-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763161 SCV000893748 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral absence of the vas deferens 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000271658 SCV000329252 pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing The W1282X pathogenic variant in the CFTR gene is one of the most common variants associated with classic cystic fibrosis, including pancreatic insufficiency, when found in a homozygous state or when compound heterozygous with another CFTR pathogenic variant (Moskowitz et al., 2008; Kerem et al., 1990). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. W1282X was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The pathogenic variant was not present in the homozygous state within this population. We interpret W1282X as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000007549 SCV000915208 pathogenic Cystic fibrosis 2018-09-18 criteria provided, single submitter clinical testing The CFTR c.3846G>A (p.Trp1282Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The variant was first reported by Vidaud et al. (1990) in one patient with cystic fibrosis who was a compound heterozygote for the p.Trp1282Ter variant and the common pathogenic p.Phe508del variant. Shoshani et al. (1992) later reported the p.Trp1282Ter variant on 63 chromosomes from 119 Israeli cystic fibrosis patients from 97 families, establishing the p.Trp1282Ter variant as the most common cystic fibrosis variant in the Ashkenazi Jewish population in Israel. Zielenski et al. (1995) published data from the Cystic Fibrosis Genetic Analysis Consortium showing that the p.Trp1282Ter variant appears in 535 of 43,849 CF chromosomes, with an overall frequency of 1.2%, and is the fifth most common disease-causing mutation in cystic fibrosis. ACMG guidelines published in 2004 recommend the p.Trp1282Ter variant be included in standard cystic fibrosis carrier screening. The variant is reported at a frequency of 0.00897 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the collective evidence, the p.Trp1282Ter variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000780159 SCV000917207 pathogenic not specified 2017-09-05 criteria provided, single submitter clinical testing Variant summary: The CFTR c.3846G>A (p.Trp1282X) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 46/120654 control chromosomes at a frequency of 0.0003813, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant is a common disease variant reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, including CFTR2. Taken together, this variant is classified as pathogenic.
Invitae RCV000007549 SCV000075007 pathogenic Cystic fibrosis 2018-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1282 (p.Trp1282*) of the CFTR gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs77010898, ExAC 0.07%). This variant is clearly defined as a cystic fibrosis (CF) causative allele (PMID: 23974870), and is included in the American College of Medical Genetics (ACMG) panel of CF variants (PMID: 15371902). It is one of the most common causes of cystic fibrosis, found in 2.6% of  individuals in a pan-ethnic population and 45% of individuals from the Ashkenazi Jewish population (PMID: 2475911, 15371902, 23974870). In the literature, this variant is also known as W1282X. ClinVar contains an entry for this variant (Variation ID: 7129). Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000007549 SCV000221178 pathogenic Cystic fibrosis 2014-12-15 criteria provided, single submitter clinical testing The Trp1282X variant in CFTR has been identified in numerous patients with cystic fibrosis (Viduad 1990, Kerem 1990, Hamosh 1991, Shoshani 1992). This variant is present on the American Board of Medical Genetics CFTR mutation panel (http://www.acmg.net/Pages/ACMG_Activities/stds-2002/cf.htm). This nonsense variant leads to a premature termination codon at position 1282, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria for pathogenicity.
Mendelics RCV000007549 SCV000886191 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
OMIM RCV000007549 SCV000027750 pathogenic Cystic fibrosis 1994-04-01 no assertion criteria provided literature only
PharmGKB RCV000417171 SCV000494722 drug response ataluren response - Efficacy 2016-03-23 reviewed by expert panel curation PharmGKB Level of Evidence 2A: Annotation for a variant-drug combination that qualifies for level 2B where the variant is within a VIP (Very Important Pharmacogene) as defined by PharmGKB. The variants in level 2A are in known pharmacogenes, so functional significance is more likely.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000271658 SCV000888091 pathogenic not provided 2015-11-04 criteria provided, single submitter clinical testing

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