Submissions for variant NM_001199107.2(TBC1D24):c.1547_1562del (p.Leu516fs)

gnomAD frequency: 0.00001  dbSNP: rs2065786997

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001581309	SCV001812028	likely pathogenic	not provided	2020-01-21	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 44 amino acids are lost and replaced with 1 incorrect amino acids (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001866104	SCV002179207	pathogenic	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2022-06-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TBC1D24 protein in which other variant(s) (p.Cys530Trp) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1210587). 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 creates a premature translational stop signal (p.Leu516Profs*2) in the TBC1D24 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the TBC1D24 protein.