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

gnomAD frequency: 0.00009  dbSNP: rs79746977

Total submissions: 5

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	RCV003960213	SCV004780727	likely pathogenic	TTC21B-related condition	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 (http://gnomad.broadinstitute.org/variant/2-166764256-G-A). 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.