ClinVar Miner

Submissions for variant NM_001199107.2(TBC1D24):c.983G>T (p.Arg328Met)

gnomAD frequency: 0.00001  dbSNP: rs796053404
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189697 SCV000243344 uncertain significance not provided 2014-07-21 criteria provided, single submitter clinical testing p.Arg328Met (AGG>ATG): c.983 G>T in exon 3 of the TBC1D24 gene (NM_001199107.1). A variant of unknown significance has been identified in the TBC1D24 gene. The c.983 G>T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Multiple in silico algorithms predict that c.983 G>T could potentially damage or destroy the natural donor site in exon 3 and lead to abnormal splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. If c.983 G>T does not affect gene splicing, it will result in the R328M missense substitution. The R328M variant 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. 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,INFANT-EPI panel(s).
Invitae RCV001214067 SCV001385730 uncertain significance Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24 2023-04-07 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 207510). This variant has not been reported in the literature in individuals affected with TBC1D24-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 328 of the TBC1D24 protein (p.Arg328Met). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon.

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