Submissions for variant NM_001199107.2(TBC1D24):c.871G>A (p.Ala291Thr)

gnomAD frequency: 0.00011  dbSNP: rs375307187

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189693	SCV000243340	uncertain significance	not provided	2020-11-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000695988	SCV000824529	uncertain significance	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 291 of the TBC1D24 protein (p.Ala291Thr). This variant is present in population databases (rs375307187, 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: 207506). 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 with a negative 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	RCV002314768	SCV000847464	uncertain significance	Inborn genetic diseases	2016-09-01	criteria provided, single submitter	clinical testing	The p.A291T variant (also known as c.871G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 871. The alanine at codon 291 is replaced by threonine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs375307187. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/12830) total alleles studied and 0.01% (1/8536) European American alleles. 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.
Fulgent Genetics, Fulgent Genetics	RCV000765280	SCV000896533	uncertain significance	DOORS syndrome; Familial infantile myoclonic epilepsy; Autosomal recessive nonsyndromic hearing loss 86; Developmental and epileptic encephalopathy, 16; Autosomal dominant nonsyndromic hearing loss 65	2018-10-31	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818460	SCV002066887	uncertain significance	not specified	2017-11-01	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252363	SCV001428118	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing