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

gnomAD frequency: 0.00022  dbSNP: rs199700840

Total submissions: 6

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, this alteration is predicted to be tolerated by in silico analysis. 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