Submissions for variant NM_024753.5(TTC21B):c.2587C>T (p.Arg863Trp)

gnomAD frequency: 0.00108  dbSNP: rs34489989

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000509503	SCV000227718	uncertain significance	not provided	2016-11-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000398651	SCV000417621	uncertain significance	Asphyxiating thoracic dystrophy 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000304805	SCV000417622	uncertain significance	Nephronophthisis 12	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000634201	SCV000755504	likely benign	Jeune thoracic dystrophy; Nephronophthisis	2025-01-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000509503	SCV001157190	uncertain significance	not provided	2019-12-10	criteria provided, single submitter	clinical testing	The TTC21B c.2587C>T; p.Arg863Trp variant (rs34489989) has been described in an individual who reportedly fulfilled diagnostic inclusion criteria for Bardet-Biedl syndrome (Redin 2012). It is reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variation ID: 195531), and is observed in the general population at an overall frequency of 0.084% (237/282480 alleles), with increased frequency in the non-Finnish European population (0.17%) in the Genome Aggregation Database. The arginine at codon 863 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious to protein structure/function. However, due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Redin C et al. Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström syndromes. J Med Genet 2012;9(8):502-512.
GeneDx	RCV000509503	SCV001776469	uncertain significance	not provided	2024-06-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported previously in the heterozygous state in an individual with Bardet-Biedl syndrome; however, no second variant was identified (PMID: 22773737); This variant is associated with the following publications: (PMID: 22773737)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000398651	SCV002768378	uncertain significance	Asphyxiating thoracic dystrophy 4	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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, PMIDs: 24876116, 21258341). (I) 0106 - This gene is associated with autosomal recessive disease. Although OMIM refers to the association of this gene with autosomal dominant nephronophthisis 12 (MIM#613820), no specific evidence was found in the literature confirming this observation. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 237 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.R863Q: 11 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated TPR-repeat motif (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a variant of uncertain significance by clinical diagnostic laboratories and is heterozygous in one individual with autosomal recessive Bardet-Biedl syndrome, with no classification provided (ClinVar, PMID: 22773737). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV000509503	SCV003821649	uncertain significance	not provided	2020-02-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000509503	SCV004147153	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TTC21B: PM2
GenomeConnect, ClinGen	RCV000509503	SCV000607229	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000509503	SCV001742808	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000509503	SCV001799234	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537393	SCV004743635	likely benign	TTC21B-related disorder	2024-01-31	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).