Submissions for variant NM_001199107.2(TBC1D24):c.1457G>A (p.Arg486His)

gnomAD frequency: 0.00001  dbSNP: rs796053405

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766893	SCV000243347	uncertain significance	not provided	2014-04-11	criteria provided, single submitter	clinical testing	p.Arg480His (CGC>CAC): c.1439 G>A in exon 6 of the TBC1D24 gene (NM_020705.2). A variant of unknown significance has been identified in the TBC1D24 gene. The R480H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R480H substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R480H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000189700	SCV000272472	uncertain significance	not specified	2015-05-05	criteria provided, single submitter	clinical testing	The p.Arg486His variant in TBC1D24 has not been previously reported in individua ls with hearing loss. Data from large population studies are insufficient to ass ess the frequency of this variant. Computational prediction tools and conservati on analysis suggest that this variant may impact the protein, though this inform ation is not predictive enough to determine pathogenicity. In summary, the clini cal significance of the p.Arg486His variant is uncertain.
Invitae	RCV001852516	SCV002214077	uncertain significance	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2021-03-30	criteria provided, single submitter	clinical testing	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 expected to disrupt TBC1D24 protein function. This variant has not been reported in the literature in individuals with TBC1D24-related conditions. ClinVar contains an entry for this variant (Variation ID: 207513). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 486 of the TBC1D24 protein (p.Arg486His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.
CeGaT Center for Human Genetics Tuebingen	RCV000766893	SCV004144814	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing	TBC1D24: PM2