ClinVar Miner

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

gnomAD frequency: 0.00108  dbSNP: rs34489989
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Total submissions: 12
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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.
Invitae RCV000634201 SCV000755504 likely benign Jeune thoracic dystrophy; Nephronophthisis 2024-01-24 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 2020-12-24 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 (Redin et al., 2012); 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 Omics 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

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