ClinVar Genomic variation as it relates to human health

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 227 of the TBC1D24 protein (p.Arg227Trp). This variant is present in population databases (rs748302886, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive TBC1D24-related conditions (PMID: 27281533, 31112829; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 429630). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg227 amino acid residue in TBC1D24. Other variant(s) that disrupt this residue have been observed in individuals with TBC1D24-related conditions (PMID: 27281533), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

The c.679C>T (p.R227W) alteration is located in exon 2 (coding exon 1) of the TBC1D24 gene. This alteration results from a C to T substitution at nucleotide position 679, causing the arginine (R) at amino acid position 227 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD) database, the TBC1D24 c.679C>T alteration was observed in <0.01% (3/249280) of total alleles studied, with a frequency of <0.01% (1/30602) in the South Asian subpopulation. This variant was identified in an individual with multifocal epilepsy in conjunction with p.A515V; however, the phase was not provided (Balestrini, 2016). It was also identified in conjunction with p.P135L in at least one Chinese individual with epilepsy (Zhang, 2019; Zhang, 2021). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Fischer, 2016). The in silico prediction for the p.R227W alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.

Reported previously in an individual with generalized and focal seizures, intellectual disability, ataxia, and progessive gait deterioration who had a second TBC1D24 variant identified; however phase was not reported (PMID: 27281533); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28428906, 31112829, 30180405, 29655203, 27669036, 33063868, 27281533)

The TBC1D24 p.Arg227Trp variant was identified in dbSNP (ID: rs748302886) and in ClinVar where it was classified as likely pathogenic by GeneDx and as a VUS by Invitae for epileptic encephalopathy, early infantile and deafness, autosomal dominant. The variant was also identified in Cosmic with a FATHMM prediction of pathogenic (score 0.98) and in LOVD 3.0 where the variant was suggested to probably affect protein function. The variant was identified in control databases in 3 of 249280 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 1 of 30602 chromosomes (freq: 0.000033) and European (non-Finnish) in 2 of 113080 chromosomes (freq: 0.000018); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish) and Other populations. This variant was identified in the compound heterozygous state (along with the TBC1D24 p.A515V variant) in a patient with clonic, focal seizures beginning at three months of age, consistent with the autosomal recessive inheritance pattern of epileptic encephalopathy, early infantile, type 16 associated with the TBC1D24 gene (Balestrini_2016_PMID: 27281533). Another variant at the same codon, p.R227Q, as well as a variant in a nearby codon, p.F229S, were both found in the Human Gene Mutation Database to be associated with TBC1D24-related disorders (Stenson_2014_PMID: 24077912). Functional co-immunoprecipitation studies of the p.F229 variant, found within the TBC domain, showed impaired TBC1D24 protein function (Milh_2013_PMID: 23526554). Additionally, ClinVar benign variants in this well-established functional TBC domain were synonymous. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Arg227 residue is conserved across mammals and other organisms, and all five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) suggest that the variant may impact the protein. In summary, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

Variant classified as Uncertain significance and reported on 12-08-2015 by Fulgent Diagnostics . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.