ClinVar Miner

Submissions for variant NM_001199107.2(TBC1D24):c.1525G>A (p.Gly509Arg) (rs749994791)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000488051 SCV000575032 uncertain significance not provided 2016-12-01 criteria provided, single submitter clinical testing
Invitae RCV000704799 SCV000833766 uncertain significance Epileptic encephalopathy, early infantile, 1; Deafness, autosomal dominant 65; Caused by mutation in the TBC1 domain family, member 24 2018-02-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 509 of the TBC1D24 protein (p.Gly509Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 7 of the TBC1D24 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs749994791, ExAC 0.02%). This variant has not been reported in the literature in individuals with TBC1D24-related disease. ClinVar contains an entry for this variant (Variation ID: 425091). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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.

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