ClinVar Miner

Submissions for variant NM_001199107.2(TBC1D24):c.1282G>A (p.Gly428Arg)

gnomAD frequency: 0.00001  dbSNP: rs2065776554
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003783683 SCV004571033 uncertain significance Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24 2023-10-10 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 428 of the TBC1D24 protein (p.Gly428Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DOORS syndrome (PMID: 29176366). 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 expected to disrupt TBC1D24 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.
GeneDx RCV004784179 SCV005396879 uncertain significance not provided 2024-05-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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: 31257402, 34341188, 35149262, 29176366, 36515421)
Neuberg Centre For Genomic Medicine, NCGM RCV004818412 SCV005439010 uncertain significance Developmental and epileptic encephalopathy, 16 2023-06-22 criteria provided, single submitter clinical testing The observed missense variant c.1282G>Ap.Gly428Arg in the TBC1D24 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in the gnomAD Exomes. The amino acid Gly at position 428 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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