Submissions for variant NM_024753.5(TTC21B):c.2693G>A (p.Arg898Gln)

gnomAD frequency: 0.00006  dbSNP: rs574017249

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001131237	SCV001290853	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.
Illumina Laboratory Services, Illumina	RCV001131238	SCV001290854	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857885	SCV002299896	uncertain significance	Jeune thoracic dystrophy; Nephronophthisis	2022-08-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 898 of the TTC21B protein (p.Arg898Gln). This variant is present in population databases (rs574017249, gnomAD 0.008%). This missense change has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446691). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Dan Cohn Lab, University Of California Los Angeles	RCV000515927	SCV000612126	uncertain significance	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515927	SCV001479705	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004735584	SCV005354210	uncertain significance	TTC21B-related disorder	2024-08-06	no assertion criteria provided	clinical testing	The TTC21B c.2693G>A variant is predicted to result in the amino acid substitution p.Arg898Gln. This variant has been reported in an individual with asphyxiating thoracic dystrophy who also carries a missense change in DYNC2H1 (Table S3. Zhang et al 2018. PubMed ID: 29068549). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.