Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000485259 | SCV000568795 | uncertain significance | not provided | 2021-05-24 | criteria provided, single submitter | clinical testing | Reported previously in an individual with Bardet-Biedl syndrome; however, a second variant was not identified in TTC21B, and this individual had two variants identified in the BBS1 gene (Davis et al., 2011).; Functional studies suggest that I1208S may result in loss of protein function (Davis et al., 2011).; 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: 21258341) |
| ARUP Laboratories, |
RCV000485259 | SCV001471082 | uncertain significance | not provided | 2019-12-19 | criteria provided, single submitter | clinical testing | The TTC21B c.3623T>G; p.Ile1208Ser variant (rs189519760) has been described in an individual with Bardet-Biedl syndrome who harbored biallelic BBS1 variants and no additional TTC21B variants (Davis 2011). In this study, the authors aimed to determine if TTC21B alleles can act as disease modifiers in patients with ciliopathy disorders. Results from in vitro analyses indicate that the p.Ile1208Ser variant may result in loss of protein function (Davis 2011). This variant is reported as a variant of uncertain significance in ClinVar (Variation ID: 420152) and is observed in the general population at an overall frequency of 0.016% (45/282498 alleles) in the Genome Aggregation Database. The isoleucine at codon 1208 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. While current studies may insist that this variant contributes to the phenotype observed in certain ciliopathies, a causative role in short-rib thoracic dysplasia has not yet been observed. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. REFERENCES Davis E et al. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet. 2011 Mar;43(3):189-96. |
| Labcorp Genetics |
RCV001851182 | SCV002169859 | uncertain significance | Jeune thoracic dystrophy; Nephronophthisis | 2022-08-02 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1208 of the TTC21B protein (p.Ile1208Ser). This variant is present in population databases (rs189519760, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with TTC21B-related conditions. ClinVar contains an entry for this variant (Variation ID: 420152). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects TTC21B function (PMID: 21258341). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. |
| Fulgent Genetics, |
RCV002489156 | SCV002787384 | uncertain significance | Asphyxiating thoracic dystrophy 4; Nephronophthisis 12 | 2024-04-12 | criteria provided, single submitter | clinical testing |