ClinVar Miner

Submissions for variant NM_024665.7(TBL1XR1):c.441T>G (p.Asp147Glu)

gnomAD frequency: 0.00001  dbSNP: rs1197826368
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001587104 SCV001819912 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
New York Genome Center RCV002227529 SCV002506922 uncertain significance Intellectual disability, autosomal dominant 41 2021-04-16 criteria provided, single submitter clinical testing The c.441T>G (p.Asp147Glu) variant identified in the TBL1XR1 gene substitutes a moderately conserved Aspartic Acid for Glutamic Acid at amino acid 147/515 (exon 7/17). This variant is found with low frequency in gnomAD(v3.1.1) (1 heterozygote, 0 homozygotes; allele frequency: 6.57e-6) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score:0.455) and Benign (REVEL; score: 0.105) to the function of the canonical transcript. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. The p.Asp147 residue is not within a mapped domain of TBL1XR1 (UniProtKB:Q9BZK7). Given the lack of compelling evidence for its pathogenicity, the c.441T>G (p.Asp147Glu) variant identified in the TBL1XR1 gene is reported as a Variant of Uncertain Significance.AS51
Invitae RCV003106240 SCV003782513 uncertain significance Pierpont syndrome 2023-05-19 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with TBL1XR1-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TBL1XR1 protein function. ClinVar contains an entry for this variant (Variation ID: 1216723). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 147 of the TBL1XR1 protein (p.Asp147Glu).

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