ClinVar Miner

Submissions for variant NM_001080522.2(CC2D2A):c.3055C>T (p.Arg1019Ter) (rs370880399)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000201572 SCV000256343 pathogenic Joubert syndrome 9 2015-02-23 criteria provided, single submitter research
GeneDx RCV000489696 SCV000577190 pathogenic not provided 2018-08-02 criteria provided, single submitter clinical testing The R1019X variant in the CC2D2A gene has been reported previously in association with Joubert syndrome and related disorders, in affected individuals who were compound heterozygous for the R1019X variant and another variant (Gorden et al., 2008; Bachmann-Gagescu et al., 2015). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1019X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R1019X as a pathogenic variant.
Invitae RCV000702498 SCV000831354 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2019-01-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1019*) in the CC2D2A gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs370880399, ExAC 0.02%). This variant has been reported as homozygous or in combination with another CC2D2A variant in several individuals affected with Joubert syndrome (PMID: 18950740, 22241855, 26092869, 27082236). ClinVar contains an entry for this variant (Variation ID: 217602). Loss-of-function variants in CC2D2A are known to be pathogenic (PMID: 19777577). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763524 SCV000894336 pathogenic Joubert syndrome with hepatic defect; Meckel syndrome type 6; Joubert syndrome 9 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778722 SCV000915078 likely pathogenic CC2D2A-Related Disorders 2018-11-30 criteria provided, single submitter clinical testing The CC2D2A c.3055C>T (p.Arg1019Ter) variant is a stop-gained variant that is predicted to cause premature truncation of the protein. This variant has been identified in at least four probands with Joubert syndrome, including in three in a compound heterozygous state with a missense variant and in one in a heterozygous state where a second variant was not detected (Gorden et al. 2008; Bachmann-Gagescu et al. 2012; Bachmann-Gagescu et al. 2015). The p.Arg1019Ter variant has also been reported in a homozygous state as a result of a different nucleotide substitution in one individual with Joubert syndrome (Ben-Salem et al. 2014). Control data are unavailable for this variant which is reported at a frequency of 0.00025 in the total population of the Exome Sequencing Project. Based on the evidence and due to the potential impact of stop-gained variants, the p.Arg1019Ter variant is classified as likely pathogenic for CC2D2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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