ClinVar Miner

Submissions for variant NM_001199107.2(TBC1D24):c.1028A>C (p.Glu343Ala)

gnomAD frequency: 0.00002  dbSNP: rs188124777
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726073 SCV000243345 uncertain significance not provided 2021-11-29 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
Eurofins Ntd Llc (ga) RCV000726073 SCV000341744 uncertain significance not provided 2016-06-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000189698 SCV000711639 uncertain significance not specified 2016-10-06 criteria provided, single submitter clinical testing The p.Glu343Ala variant in TBC1D24 has not been previously reported in individua ls with hearing loss, but has been identified in 6/7238 East Asian chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs188124777). However, this frequency is not high enough to rule out a pathogen ic role. Computational prediction tools and conservation analysis suggest that t he p.Glue343Ala variant may not impact the protein, though this information is n ot predictive enough to rule out pathogenicity. In summary, the clinical signifi cance of the p.Glu343Ala variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp RCV000651570 SCV000773424 uncertain significance Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24 2023-12-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 343 of the TBC1D24 protein (p.Glu343Ala). This variant is present in population databases (rs188124777, gnomAD 0.04%). 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: 207511). 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 RCV002381644 SCV002692257 uncertain significance Inborn genetic diseases 2024-10-01 criteria provided, single submitter clinical testing The p.E343A variant (also known as c.1028A>C), located in coding exon 3 of the TBC1D24 gene, results from an A to C substitution at nucleotide position 1028. The glutamic acid at codon 343 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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