Submissions for variant NM_024753.5(TTC21B):c.1320del (p.Phe440fs)

dbSNP: rs775836730

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001074968	SCV001240575	likely pathogenic	Retinal dystrophy	2017-09-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851419	SCV002234176	pathogenic	Jeune thoracic dystrophy; Nephronophthisis	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe440Leufs*4) 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 (rs775836730, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with short-rib polydactyly syndrome type IV (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446650). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496988	SCV002806462	pathogenic	Asphyxiating thoracic dystrophy 4; Nephronophthisis 12	2024-04-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787820	SCV005399668	pathogenic	Asphyxiating thoracic dystrophy 4	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nephronophthisis 12 (MIM#613820), short-rib thoracic dysplasia 4 with or without polydactyly (MIM#613819) and familial focal segmental glomerulosclerosis (FSGS). Partial loss of function has also been described, and associated with hypomorphic variants in this gene (OMIM, PMID: 24876116, 21258341). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (11 heterozygotes, 0 homozygotes). (SP) 0701 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. This variant has also been identified in a compound heterozygote neonate with short-rib polydactyl syndrome type IV (PMID: 29068549). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Dan Cohn Lab, University Of California Los Angeles	RCV000516032	SCV000612064	pathogenic	Type IV short rib polydactyly syndrome	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000516032	SCV001480012	likely pathogenic	Type IV short rib polydactyly syndrome		no assertion criteria provided	research