ClinVar Miner

Submissions for variant NM_001199107.2(TBC1D24):c.119G>T (p.Arg40Leu)

gnomAD frequency: 0.00001  dbSNP: rs760474458
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Total submissions: 4
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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 RCV000192066 SCV000266465 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.
Invitae RCV001850282 SCV002311889 likely pathogenic Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24 2023-03-20 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg40 amino acid residue in TBC1D24. Other variant(s) that disrupt this residue have been observed in individuals with TBC1D24-related conditions (PMID: 24291220; Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TBC1D24 function (PMID: 27281533, 30335140). 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: 183152). This missense change has been observed in individual(s) with autosomal recessive DOORS syndrome (PMID: 24291220). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 40 of the TBC1D24 protein (p.Arg40Leu).
Division of Medical Genetics; Sainte-Justine Hospital RCV000192066 SCV000211964 pathogenic DOORS syndrome 2014-12-22 no assertion criteria provided literature only
GeneReviews RCV000192066 SCV002106357 not provided DOORS syndrome no assertion provided literature only

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