ClinVar Miner

Submissions for variant NM_024753.5(TTC21B):c.2500C>T (p.Gln834Ter)

gnomAD frequency: 0.00009  dbSNP: rs79746977
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002525013 SCV002940654 pathogenic Jeune thoracic dystrophy; Nephronophthisis 2023-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln834*) in the TTC21B gene. It is expected to result in an absent or disrupted protein product. 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 (rs79746977, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with short-rib polydactyly syndromes (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446649). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV004541600 SCV004780727 likely pathogenic TTC21B-related disorder 2023-11-08 criteria provided, single submitter clinical testing The TTC21B c.2500C>T variant is predicted to result in premature protein termination (p.Gln834*). This variant was reported in compound heterozygous state in an individual with short rib-polydactyly syndrome (Patient R08-045A in Table S2, Zhang et al. 2018. PubMed ID: 29068549) and in two siblings with early onset hypertension and tubuloglomerular kidney disease (Olinger et al. 2022. PubMed ID: 35289079). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD ( Nonsense variants in TTC21B are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Dan Cohn Lab, University Of California Los Angeles RCV000515936 SCV000612063 pathogenic Short-rib thoracic dysplasia 6 with or without polydactyly 2017-06-01 no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000515936 SCV001479579 likely pathogenic Short-rib thoracic dysplasia 6 with or without polydactyly no assertion criteria provided research
Genetic Services Laboratory, University of Chicago RCV003151077 SCV003839185 likely pathogenic not provided 2022-08-16 no assertion criteria provided clinical testing DNA sequence analysis of the TTC21B gene demonstrated a sequence change, c.2500C>T, which results in the creation of a premature stop codon at amino acid position 834, p.Gln834*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated TTC21B protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.006% in the overall population (rs115348383). This sequence change has previously been described in the compound heterozygous state in an individual with short-rib polydactyly syndrome type II (PMID: 29068549).This collective evidence indicates that this sequence change is likely pathogenic; however, functional studies have not been performed to determine this conclusively. This sequence change in the heterozygous state is not sufficient to cause autosomal recessive TTC21B-related disorders. However, the contribution of a single pathogenic sequence change in TTC21B remains unclear at this time.

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