ClinVar Miner

Submissions for variant NM_001199107.2(TBC1D24):c.829G>A (p.Ala277Thr)

gnomAD frequency: 0.00001  dbSNP: rs754019727
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000538988 SCV000654218 uncertain significance Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24 2022-08-15 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: 474314). This variant has not been reported in the literature in individuals affected with TBC1D24-related conditions. This variant is present in population databases (rs754019727, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 277 of the TBC1D24 protein (p.Ala277Thr).
Ambry Genetics RCV002316579 SCV000851215 uncertain significance Inborn genetic diseases 2016-09-01 criteria provided, single submitter clinical testing The p.A277T variant (also known as c.829G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 829. The alanine at codon 277 is replaced by threonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6428 samples (12856 alleles) with coverage at this position. 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.

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