Submissions for variant NM_024753.5(TTC21B):c.691A>T (p.Thr231Ser)

gnomAD frequency: 0.00071  dbSNP: rs149925563

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724482	SCV000231791	uncertain significance	not provided	2015-02-12	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000179530	SCV000249228	uncertain significance	not specified	2017-04-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000724482	SCV000730615	likely benign	not provided	2021-02-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26940125, 21258341, 27884173, 30037327)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000724482	SCV000884766	uncertain significance	not provided	2018-02-16	criteria provided, single submitter	clinical testing	The c.691A>T; p.Thr231Ser variant has been reported in the heterozygous state in 8 patients diagnosed with a range of ciliopathies, including Jeune asphyxiating thoracic dystrophy (JATD), Meckel-Gruber Syndrome (MKS), Bardet-Biedl syndrome (BBS - 4 individuals), and nephronophthisis (NPHP - 2 individuals) (Davis 2011). The results of functional studies in zebrafish embryos and human cell lines resulted in this variant being classified as a hypomorphic allele (Davis 2011). It is classified as a variant of unknown significance in ClinVar (ID: 198257). However, this variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.1% (identified on 280 out of 277,060 chromosomes, including 2 homozygotes), and was found in the Saudi Human Genome Program with a population frequency of 1.5% (identified on 53 out of 3504 chromosomes, including 2 homozygotes) (Abouelhoda 2016). This variant was also reported in a patient with Alport syndrome who also carried two pathogenic variants in the COL4A3 gene (Bullich 2017). The threonine at position 231 is moderately conserved, considering 11 species, and computational analyses of the effects of the p.Thr231Ser variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Although population frequencies argue against pathogenicity, the clinical significance of the p.Thr231Ser variant cannot be determined with certainty.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087340	SCV001002106	benign	Jeune thoracic dystrophy; Nephronophthisis	2024-01-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000986867	SCV001136012	uncertain significance	Joubert syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001132638	SCV001292305	uncertain significance	Asphyxiating thoracic dystrophy 4	2017-04-27	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001132639	SCV001292306	uncertain significance	Nephronophthisis 12	2017-04-27	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000724482	SCV004147159	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TTC21B: BP4
PreventionGenetics, part of Exact Sciences	RCV004537489	SCV004749417	likely benign	TTC21B-related disorder	2022-07-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).