ClinVar Miner

Submissions for variant NM_001199107.2(TBC1D24):c.724C>T (p.Arg242Cys) (rs398122965)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189686 SCV000243332 pathogenic not provided 2017-10-30 criteria provided, single submitter clinical testing p.Arg242Cys (CGC>TGC): c.724 C>T in exon 2 of the TBC1D24 gene (NM_020705.2). The R242C missense mutation in the TBC1D24 gene has been reported previously in association with with DOORS syndrome in multiple unrelated individuals who were homozygous or compound heterozygous for R242C and another mutation (Campeau et al., 2014). The R242C substitution was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a non-conservative amino acid substitution at a conserved residue. Therefore, R242C is considered a disease-causing mutation. The variant is found in CHILD-EPI panel(s).
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000076913 SCV000266460 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.
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000585843 SCV000693777 likely pathogenic Early infantile epileptic encephalopathy 16 2018-01-01 criteria provided, single submitter clinical testing
Invitae RCV000651571 SCV000773425 likely pathogenic Epileptic encephalopathy, early infantile, 1; Deafness, autosomal dominant 65; Caused by mutation in the TBC1 domain family, member 24 2017-08-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 242 of the TBC1D24 protein (p.Arg242Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs398122965, ExAC 0.002%). This variant has been reported as homozygous and/or in combination with other TBC1D24 variants in several individuals affected with Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome  (PMID: 24291220). ClinVar contains an entry for this variant (Variation ID: 91395). Experimental studies have shown that this missense change leads to a significant reduction in neurite length compared to wildtype (PMID: 27281533). 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.
OMIM RCV000076913 SCV000108710 pathogenic DOORS syndrome 2014-01-01 no assertion criteria provided literature only
Division of Medical Genetics; Sainte-Justine Hospital RCV000076913 SCV000211967 pathogenic DOORS syndrome 2014-12-22 no assertion criteria provided literature only

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