ClinVar Miner

Submissions for variant NM_001080522.2(CC2D2A):c.3975+4_3975+7del (rs386833759)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000201729 SCV000256362 pathogenic Joubert syndrome 9 2015-02-23 criteria provided, single submitter research
Invitae RCV000800604 SCV000940330 likely pathogenic Joubert syndrome; Meckel-Gruber syndrome 2018-09-06 criteria provided, single submitter clinical testing This sequence change falls in intron 31 of the CC2D2A gene. It does not directly change the encoded amino acid sequence of the CC2D2A protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in one of the individuals affected with clinical features of Meckel-Gruber syndrome, and in another individual affected with Joubert syndrome (PMID: 26092869, 19466712, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as c.3975delA+1_3delGTA in the literature. ClinVar contains an entry for this variant (Variation ID: 217617). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049723 SCV000082130 probable-pathogenic Meckel syndrome type 6 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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