ClinVar Miner

Submissions for variant NM_001199107.2(TBC1D24):c.878G>A (p.Arg293His)

gnomAD frequency: 0.00022  dbSNP: rs199700840
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189706 SCV000243353 uncertain significance not provided 2020-11-09 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; A different missense change at this residue (R293P) has been reported in the homozygous state in a family with nonsyndromic hearing loss, however seizure history was not evaluated (Rehman et al., 2014); Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000551334 SCV000654219 uncertain significance Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24 2023-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 293 of the TBC1D24 protein (p.Arg293His). This variant is present in population databases (rs199700840, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TBC1D24-related conditions. ClinVar contains an entry for this variant (Variation ID: 207519). 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 with a positive predictive value of 80%. 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.
Ambry Genetics RCV002317660 SCV000851060 uncertain significance Inborn genetic diseases 2019-06-06 criteria provided, single submitter clinical testing The p.R293H variant (also known as c.878G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 878. The arginine at codon 293 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002478665 SCV000896534 uncertain significance Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer's cramp syndrome; DOORS syndrome; Familial infantile myoclonic epilepsy; Autosomal recessive nonsyndromic hearing loss 86; Developmental and epileptic encephalopathy, 16; Autosomal dominant nonsyndromic hearing loss 65 2022-01-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000826046 SCV000967538 uncertain significance not specified 2019-02-13 criteria provided, single submitter clinical testing The p.Arg293His variant in TBC1D24 has not been previously reported in individuals with hearing loss or DOORS syndrome, but has been identified in 0.034% (43/128356) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 207519). A different missense variant at the same position (p.Arg293Pro) has been reported to segregate with hearing loss in a Pakistani family (Rehman 2014). Computational prediction tools and conservation analysis suggest that the p.Arg293His variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5_Supporting, PM2_Supporting, PP3.
CeGaT Center for Human Genetics Tuebingen RCV000189706 SCV004144807 uncertain significance not provided 2022-06-01 criteria provided, single submitter clinical testing TBC1D24: PM2, PM5

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