ClinVar Miner

Submissions for variant NM_025114.3(CEP290):c.384_387delTAGA (p.Asp128Glufs) (rs386834157)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000779119 SCV000915613 pathogenic CEP290-Related Disorders 2018-12-04 criteria provided, single submitter clinical testing The CEP290 c.384_387delTAGA (p.Asp128GlufsTer34) variant causes a frameshift and results in a premature truncation of the protein. The p.Asp128GlufsTer34 variant has been reported in four studies in which it is found in a total of seven individuals, including two homozygotes and five compound heterozygotes (Baala et al. 2007; Perrault et al. 2007; Aguilar et al. 2012; Sheck et al. 2018). Five of the individuals presented with brain abnormalities, including Dandy-Walker malformation, occipital meningocele, or cerebellar vermis hypoplasia, and were diagnosed with Meckel syndrome or Joubert syndrome upon fetal autopsy, while one 5-month old individual was reported to have normal development and was diagnosed with Leber congeital amaurosis upon clinical exam. The p.Asp128GlufsTer34variant was absent from 96 controls (Perrault et al. 2007) and is reported at a frequency of 0.01304 in the European American population of the Exome Sequencing Project. However, this frequency is orders of magnitude higher than the highest frequency reported in the Exome Aggregation Consortium, where the p.Asp128GlufsTer34 variant is found at a frequency of 0.00009 in the European (non-Finnish) population. Based on the potential impact of frameshift variant and collective clinical evidence, the p.Asp128GlufsTer34 variant is classified as pathogenic for CEP290-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000702996 SCV000831875 pathogenic Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis 2017-10-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp128Glufs*34) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs386834157, ExAC 0.009%). This variant has been reported to segregate with Meckel syndrome in several families (PMID: 17564974) and has also been reported in individuals with Leber congenital amaurosis (PMID: 17345604, 21602930). It is also known as 383_386delATAG in the literature.  ClinVar contains an entry for this variant (Variation ID: 56738). Loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000050151 SCV000082561 probable-pathogenic Meckel syndrome type 4 no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000416432 SCV000494244 pathogenic Joubert syndrome 5 2016-06-28 criteria provided, single submitter clinical testing The c.384_387delTAGA (p.Asp128Glufs*34) frameshift variant in the CEP290 gene has been previously reported in one family affected with Leber Congenital Amaurosis and two families affected with Meckel Syndrome (Baala et al., 2007; Perrault et al., 2007). In two unrelated individuals, this variant was observed in trans with other pathogenic variants (Cys998Ter, c.180+2T>A) (Baala et al., 2007; Perrault et al., 2007). This frameshift variant is predicted truncate the protein product, and loss of function variants, including variants downstream of this one, have been reported as a common mechanism of disease. This variant is reported at low frequency in the population databases (Exome Sequencing Project = NA; 1000 Genomes = NA; and ExAC = 0.009%). Therefore, this collective evidence supports the classification of the c.384_387delTAGA (p.Asp128Glufs*34) as a Pathogenic variant for Joubert Syndrome and Related Diseases. We have confirmed this finding in our laboratory using Sanger sequencing.

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