ClinVar Genomic variation as it relates to human health

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 roadinstitute.org; 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.

For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TBC1D24 protein function. ClinVar contains an entry for this variant (Variation ID: 207499). This missense change has been observed in individuals with autosomal recessive TBC1D24-related conditions (PMID: 25769375, 26371875, 28428906). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs376712059, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 153 of the TBC1D24 protein (p.Glu153Lys).

The p.E153K variant (also known as c.457G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 457. The glutamic acid at codon 153 is replaced by lysine, an amino acid with similar properties. This alteration was detected in the homozygous state in two brothers of Algerian descent from a consanguineous family with early onset focal myoclonic fits that evolved to generalized myoclonus, developmental delay, moderate learning concerns, and a diagnosis of familial infantile myoclonic epilepsy; however, TBC1D24 was the only gene analyzed (Poulat AL, Epilepsy Res. 2015 Mar; 111:72-7). In addition, this alteration was detected in trans with another alteration in the TBC1D24 via whole exome sequencing in two siblings with nonsyndromic hearing loss (Bakhchane A, PLoS ONE 2015; 10(9):e0138072). This variant was previously reported in the SNPDatabase as rs376712059. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/12876) total alleles studied and 0.01% (1/8536) European American alleles. Based on data from ExAC, the A allele has an overall frequency of approximately <0.01% (8/104258) total alleles studied (TCGA excluded). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this variant remains unclear.

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24291220, 27259978, 25769375, 28428906, 32004315, 28292732, 27652284, 27281533, 31216405, 33619735, 34852372, Timpanaro2021[Review], 28726039, 33986365, 35350397, 34926809, 37538433, Mehdaoui2023[casereport], Vetri2024[casereport], 38923778, 26371875)

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with epileptic encephalopathy and appears to segregate with disease in at least one family with infantile myoclonic epilepsy. Computational tools predict that this variant is damaging.

Criteria applied: PS1,PS4_MOD,PM2_SUP