ClinVar Miner

Submissions for variant NM_001199107.2(TBC1D24):c.457G>A (p.Glu153Lys) (rs376712059)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189685 SCV000243331 likely pathogenic not provided 2018-10-08 criteria provided, single submitter clinical testing The E153K variant in the TBC1D24 gene has been reported in the homozygous state in two siblings with familial infantile myoclonic epilepsy (FIME) and moderate intellectual disability; however, functional studies were not performed (Poulat et al., 2015). The E153K variant has also been reported in the compound heterozygous state in unrelated individuals with epilepsy and in two siblings with nonsyndromic hearing loss (de Kovel et al., 2016; Ngoh et al., 2017; Bakhchane et al., 2015). The E153K variant is observed in 17/243058 (0.007%) alleles in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). The E153K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. We interpret E153K as a likely pathogenic variant.
Invitae RCV000558935 SCV000654208 uncertain significance Epileptic encephalopathy, early infantile, 1; Deafness, autosomal dominant 65; Caused by mutation in the TBC1 domain family, member 24 2017-07-03 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 153 of the TBC1D24 protein (p.Glu153Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs376712059, ExAC 0.05%). This variant has been reported as homozygous in two siblings affected with infantile-onset myoclonic epilepsy (PMID: 25769375), and in combination with another TBC1D24 variant (p.Arg214His) in two siblings affected with non-syndrome sensorineuronal hearing loss (PMID: 26371875). ClinVar contains an entry for this variant (Variation ID: 207499). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000614904 SCV000711638 likely pathogenic Rare genetic deafness 2017-11-13 criteria provided, single submitter clinical testing The p.Glu153Lys variant in TBC1D24 has been indentified in 5 individuals with TB C1D24-associated features. One individual had nonsyndromic hearing loss and was compound heterozygote for this variant as well as a VUS variant, both of which s egregated in a sibling with hearing loss (Bakhchane 2015). This variant has now been identified by our laboratory in an individual with hearing loss in trans wi th a TBC1D24 variant of uncertain significance (LMM data). Another individual p resented with a seizure disorder who initially passed an early hearing screen bu t developed profound deafness reported by 5 years of age (Ngoh 2017). This indiv idual was compound heterozygous for the p.Glu153Lys variant and a pathogenic var iant in TBC1D24, and both variants segregated in a sibling with similar seizure manifestations but was not reported to have hearing loss at 3 years of age (Ngoh 2017). In addition, the variant was reported in one homozygote individual and h is sibling (Poulat 2015), and one compound heterozygote individual (Ragona 2017) , all presenting with TBC1D24-related seizures, but hearing loss was not reporte d. The p.Glu153Lys variant has been identified in 3/20274 Finnish and 12/110864 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b; dbSNP rs376712059), and has been reported in ClinVar (Variati on ID 207499). Although there is a wide range of clinical features reported for affected individuals that carry this variant, these features are consistent with the phenotypic spectrum associated with TBC1D24-associated disorders. In additi on, the segregation of the variant in similarly affected family members in three unrelated families supports a causative role for the variant. Furthermore, comp utational prediction tools and conservation analysis suggest that the p.Glu153Ly s variant may impact the protein. In summary, although additional studies are r equired to fully establish its clinical significance, this variant is likely pat hogenic. ACMG/AMP Criteria applied: PP1_S, PM3_S, PM2, PM3, PP3, PP4.
Ambry Genetics RCV000715375 SCV000846204 uncertain significance Seizures 2016-04-16 criteria provided, single submitter clinical testing Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Baylor Genetics RCV000850506 SCV000992709 likely pathogenic DOORS syndrome; Myoclonic epilepsy, familial infantile; Deafness, autosomal recessive 86; Early infantile epileptic encephalopathy 16; Deafness, autosomal dominant 65 2018-10-12 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000995887 SCV001150277 pathogenic DOORS syndrome 2019-06-07 criteria provided, single submitter clinical testing

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