ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.647G>A (p.Trp216Ter) (rs397508775)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000576668 SCV000677626 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Integrated Genetics/Laboratory Corporation of America RCV000780125 SCV000917169 pathogenic not specified 2018-09-17 criteria provided, single submitter clinical testing Variant summary: CFTR c.647G>A (p.Trp216X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 246204 control chromosomes (gnomAD and publication). The variant, c.647G>A, has been reported in the literature in multiple individuals affected with Non-classic Cystic Fibrosis, including one homozygote (Anzai_2003, Clain_2005, Claustres_2000, Kammesheidt_2006, Shen_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000780125 SCV001159831 pathogenic not specified 2018-07-18 criteria provided, single submitter clinical testing The CFTR c.647G>A; p.Trp216Ter variant (rs397508775), also known as c.779G>A in traditional nomenclature, is reported in the literature in a homozygous or compound heterozygous state in multiple individuals affected with cystic fibrosis (Clain 2005, Claustres 2000, Kammesheidt 2006, Shen 2016) or congenital bilateral absence of the vas deferens (Anzai 2003). This variant is reported as pathogenic by an expert panel in ClinVar (Variation ID: 54033), and is only observed on one allele 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 pathogenic. References: Anzai C et al. CFTR gene mutations in Japanese individuals with congenital bilateral absence of the vas deferens. J Cyst Fibros. 2003 Mar;2(1):14-8. Clain J et al. Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype. Hum Mutat. 2005 Apr;25(4):360-71. Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-56. Kammesheidt A et al. Comprehensive genetic analysis of the cystic fibrosis transmembrane conductance regulator from dried blood specimens--implications for newborn screening. Genet Med. 2006 Sep;8(9):557-62. Shen Y et al. Clinical Phenotypes and Genotypic Spectrum of Cystic Fibrosis in Chinese Children. J Pediatr. 2016 Apr;171:269-76.e1.
CFTR-France RCV000576668 SCV001169334 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000576668 SCV000679176 not provided Cystic fibrosis no assertion provided literature only

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