Submissions for variant NM_001199107.2(TBC1D24):c.1499C>T (p.Ala500Val)

gnomAD frequency: 0.00002  dbSNP: rs564477999

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481838	SCV000567005	pathogenic	not provided	2022-08-17	criteria provided, single submitter	clinical testing	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, 30108545, 31112829, 30945278, 30180405, 27281533, 31257402, 33333793, 31618474)
Invitae	RCV000800580	SCV000940306	pathogenic	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 500 of the TBC1D24 protein (p.Ala500Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of DOORS syndrome (PMID: 27281533, 30108545, 31112829, 31257402). 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: 419296). 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 not expected to disrupt TBC1D24 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000808207	SCV002579041	likely pathogenic	Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer's cramp syndrome	2022-04-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000481838	SCV003819876	pathogenic	not provided	2022-02-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479135	SCV004222673	pathogenic	TBC1D24-Related Disorders	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: TBC1D24 c.1499C>T (p.Ala500Val) results in a non-conservative amino acid change located in the TLDc domain (IPR006571) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 183122 control chromosomes (gnomAD). c.1499C>T has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with TBC1D24-Related Disorders, including several cases where it was confirmed to be in trans with a pathogenic variant (e.g. Balestrini_2016, Luthy_2019, Burgess_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27281533, 31618474, 31257402). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000808207	SCV000948303	pathogenic	Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer's cramp syndrome	2019-08-09	no assertion criteria provided	literature only
Clinical Genomics Program, Stanford Medicine	RCV000481838	SCV001427232	pathogenic	not provided	2020-04-03	no assertion criteria provided	clinical testing	The p.Ala500Val variant in the TBC1D24 gene has been previously reported in at least 8 unrelated individual(s) with TBC1D24-associated disorders (Balestrini et al., 2016; GeneDx, personal communication, March 20, 2020; Li et al., 2018; Luthy et al., 2019; Zhang et al., 2019). All affected individuals were homozygous or compound heterozygous. This variant was determined to be in trans with three likely pathogenic/pathogenic variants (p.Ile81_Lys84del; p.Ser473Argfs*43; p.Gln385Ter), consistent with autosomal recessive inheritance (Li et al., 2018; Luthy et al., 2019; Zhang et al., 2019). The presence of this variant with likely disease-causing variants on the opposite allele increases suspicion for its pathogenicity. Computational tools predict that the p.Ala500Val variant is deleterious; however, the accuracy of in silico algorithms is limited. This variant has been identified in the East Asian population in 7/15,658 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ala500Val variant as pathogenic for autosomal recessive TBC1D24-associated disorders based on the information above.[ACMG evidence codes used: PM2; PM3_verystrong; PP3]