Submissions for variant NM_024753.5(TTC21B):c.1697A>G (p.His566Arg)

gnomAD frequency: 0.00063  dbSNP: rs146320075

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174799	SCV000226169	uncertain significance	not provided	2015-04-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001078741	SCV000255123	likely benign	Jeune thoracic dystrophy; Nephronophthisis	2025-01-13	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000755750	SCV000883283	uncertain significance	Nephronophthisis 12	2018-10-15	criteria provided, single submitter	curation	This variant is interpreted as Uncertain Significance - Conflicting Evidence, for Nephronophthisis 12, autosomal recessive. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. BS1-Supporting => BS1 downgraded in strength to supporting. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/21258341).
Fulgent Genetics, Fulgent Genetics	RCV000764280	SCV000895299	uncertain significance	Asphyxiating thoracic dystrophy 4; Nephronophthisis 12	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001134339	SCV001294076	uncertain significance	Asphyxiating thoracic dystrophy 4	2017-08-21	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	RCV000755750	SCV001294077	uncertain significance	Nephronophthisis 12	2017-08-21	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	RCV000174799	SCV002496536	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	TTC21B: PM2, PP3
GeneDx	RCV000174799	SCV005324967	uncertain significance	not provided	2024-02-13	criteria provided, single submitter	clinical testing	Observed in a patient with nephronophthisis in whom a second TTC21B variant was not identified (PMID: 21258341); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 36263627, 33452237, 21258341)
PreventionGenetics, part of Exact Sciences	RCV004734779	SCV005366400	uncertain significance	TTC21B-related disorder	2024-05-08	no assertion criteria provided	clinical testing	The TTC21B c.1697A>G variant is predicted to result in the amino acid substitution p.His566Arg. This variant was reported in individuals with TTC21B-related diseases (Davis et al. 2011. PubMed ID: 21258341, Supplementary Tables; Nagaoka et al. 2021. PubMed ID: 33452237). This variant is reported in >0.25% of alleles in individuals of European (Finnish) descent in gnomAD and there are two homozygotes of this variant in individuals of European (non-Finnish) descent in the new version (v4) of gnomAD (https://gnomad.broadinstitute.org/variant/2-165917459-T-C?dataset=gnomad_r4). Although we suspect this variant may be benign due to the relatively high allele frequency in the general population, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.