Submissions for variant NM_001199107.2(TBC1D24):c.1253T>C (p.Phe418Ser)

gnomAD frequency: 0.00001  dbSNP: rs776176742

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189699	SCV000243346	uncertain significance	not provided	2014-05-21	criteria provided, single submitter	clinical testing	p.Phe412Ser (TTT>TCT): c.1235 T>C in exon 5 of the TBC1D24 gene (NM_020705.2). A variant of unknown significance has been identified in the TBC1D24 gene. The F412S 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 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and Serine is seen at this position in multiple species. In silico analysis predicts this variant likely does not alter the protein structure/function. 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).
Mayo Clinic Laboratories, Mayo Clinic	RCV000660651	SCV000782778	uncertain significance	Familial infantile myoclonic epilepsy; Developmental and epileptic encephalopathy, 16	2018-02-15	criteria provided, single submitter	clinical testing
Invitae	RCV001232819	SCV001405389	uncertain significance	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2023-06-29	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 not expected to disrupt TBC1D24 protein function. ClinVar contains an entry for this variant (Variation ID: 207512). This variant has not been reported in the literature in individuals affected with TBC1D24-related conditions. This variant is present in population databases (rs776176742, gnomAD 0.007%). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 418 of the TBC1D24 protein (p.Phe418Ser).
Ambry Genetics	RCV002415814	SCV002677374	uncertain significance	Inborn genetic diseases	2017-07-18	criteria provided, single submitter	clinical testing	The p.F418S variant (also known as c.1253T>C), located in coding exon 5 of the TBC1D24 gene, results from a T to C substitution at nucleotide position 1253. The phenylalanine at codon 418 is replaced by serine, an amino acid with highly dissimilar properties. This amino acid position is not well 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.