Submissions for variant NM_024753.5(TTC21B):c.2600G>A (p.Arg867His)

gnomAD frequency: 0.00161  dbSNP: rs76726265

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000252244	SCV000314423	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV001705374	SCV000515071	likely benign	not provided	2020-10-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27666822, 21258341)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000861928	SCV001002349	likely benign	Jeune thoracic dystrophy; Nephronophthisis	2024-01-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705374	SCV001159321	uncertain significance	not provided	2019-09-25	criteria provided, single submitter	clinical testing	The TTC21B c.2600G>A; p.Arg867His variant (rs76726265) is reported in the literature in an individual affected with Meckel-Gruber syndrome (Davis 2011), an individual with asphyxiating thoracic dystrophy (Duran 2016), as well as a healthy control (Davis 2011). However, both affected individuals carried additional pathogenic variants that could explain the observed phenotypes (Davis 2011, Duran 2016). Another variant at this codon (p.Arg867Cys) has been reported in an individual with Joubert syndrome (Davis 2011). The p.Arg867His variant is reported in ClinVar (Variation ID: 261776) and is found in the African population with an overall allele frequency of 0.49% (117/24006 alleles) in the Genome Aggregation Database. The arginine at codon 867 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In an in vivo complementation assay of zebrafish ttc21b morphant phenotypes, neither a p.Arg867His variant nor a p.Arg867Cys variant rescued developmental phenotypes as robustly as a wildtype human TTC21B control (Davis 2011). Due to conflicting information, the clinical significance of the p.Arg867His variant is uncertain at this time. References: Davis EE et al. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet. 2011 Mar;43(3):189-96. Duran I et al. Destabilization of the IFT-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short-Rib Polydactyly Syndrome. Sci Rep. 2016 Sep 26;6:34232.
Illumina Laboratory Services, Illumina	RCV001134203	SCV001293936	likely benign	Asphyxiating thoracic dystrophy 4	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001134204	SCV001293937	likely benign	Nephronophthisis 12	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001134204	SCV001984568	uncertain significance	Nephronophthisis 12	2020-08-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000252244	SCV002067920	uncertain significance	not specified	2021-09-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the TTC21B gene demonstrated a sequence change, c.2600G>A, in exon 20 that results in an amino acid change, p.Arg867His. This sequence change has been described in the gnomAD database with a frequency of 0.53% in the African/African American subpopulation (dbSNP rs76726265). The p.Arg867His change affects a highly conserved amino acid residue located in a domain of the TTC21B protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg867His substitution. This sequence change has been reported in an individual with Meckel-Gruber syndrome and in an individual with asphyxiating thoracic dystrophy (PMID: 21258341, 27666822 ). These individuals, however, also carried a pathogenic variant in another gene that could cause their phenotype. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg867His change remains unknown at this time.
CeGaT Center for Human Genetics Tuebingen	RCV001705374	SCV002496535	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing