ClinVar Miner

Submissions for variant NM_024753.5(TTC21B):c.553-2A>G

gnomAD frequency: 0.00001  dbSNP: rs773580610
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479541 SCV000573665 likely pathogenic not provided 2017-03-07 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the TTC21B gene. The c.553-2 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.553-2 A>G splice site variant destroys the canonical splice acceptor site in intron 5. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Furthermore, the c.553-2 A>G 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). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp RCV001377359 SCV001574677 likely pathogenic Jeune thoracic dystrophy; Nephronophthisis 2024-12-09 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the TTC21B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TTC21B are known to be pathogenic (PMID: 18327258, 21068128, 21258341, 23559409, 24876116, 25492405, 27491411, 29068549). This variant is present in population databases (rs773580610, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with clinical features of TTC21B-related conditions (PMID: 33323469). ClinVar contains an entry for this variant (Variation ID: 423908). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Fulgent Genetics, Fulgent Genetics RCV005018816 SCV005653371 likely pathogenic Asphyxiating thoracic dystrophy 4; Nephronophthisis 12 2024-05-30 criteria provided, single submitter clinical testing

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