ClinVar Miner

Submissions for variant NM_001199107.2(TBC1D24):c.118C>T (p.Arg40Cys)

gnomAD frequency: 0.00001  dbSNP: rs398122966
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000076914 SCV000266461 pathogenic DOORS syndrome 2014-01-01 criteria provided, single submitter research We identified 26 families with DOORS syndrome; each patient had at least 3 of the 5 well-described features of DOORS syndrome, which include deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. A combination of whole-exome sequencing and Sanger sequencing identified homozygous or compound heterozygous pathogenic variants in TBC1D24 in 11 individuals from 9 families.
GeneDx RCV001563390 SCV001786321 pathogenic not provided 2020-04-14 criteria provided, single submitter clinical testing Published in vivo functional studies of transgenic flies demonstrate reduced diffusion of Sky in presynaptic terminals, impaired trafficking of synaptic vesicles, and behavioral deficits, and in vitro functional studies demonstrate reduced binding to phosphatidylinositol 4,5-bisphosphate containing liposomes, and decreased affinity for IP3 (Fischer et al., 2016; Luthy et al., 2019); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27669036, 25169651, 31257402, 24291220)
Invitae RCV001854346 SCV002237154 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 the p.Arg40 amino acid residue in TBC1D24. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24291220; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TBC1D24 function (PMID: 27669036, 31257402). 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 expected to disrupt TBC1D24 protein function. ClinVar contains an entry for this variant (Variation ID: 91396). This missense change has been observed in individual(s) with DOORS syndrome (PMID: 24291220). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs398122966, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 40 of the TBC1D24 protein (p.Arg40Cys).
OMIM RCV000076914 SCV000108711 pathogenic DOORS syndrome 2014-01-01 no assertion criteria provided literature only
Division of Medical Genetics; Sainte-Justine Hospital RCV000076914 SCV000211963 pathogenic DOORS syndrome 2014-12-22 no assertion criteria provided literature only

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