Submissions for variant NM_001199107.2(TBC1D24):c.170G>A (p.Arg57His)

dbSNP: rs370100394

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498416	SCV000589364	uncertain significance	not provided	2016-09-22	criteria provided, single submitter	clinical testing	The R57H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R57H variant was not observed with any significant frequency in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R57H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV003766789	SCV004570866	uncertain significance	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2023-07-18	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 431832). 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 TBC1D24 protein function. This variant has not been reported in the literature in individuals affected with TBC1D24-related conditions. This variant is present in population databases (rs370100394, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 57 of the TBC1D24 protein (p.Arg57His).