Submissions for variant NM_001199107.2(TBC1D24):c.845C>G (p.Pro282Arg)

gnomAD frequency: 0.00002  dbSNP: rs747538224

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254691	SCV000243339	pathogenic	not provided	2024-06-18	criteria provided, single submitter	clinical testing	Reported previously in individuals with clinical features consistent with TBC1D24-related DOORS spectrum disorder who also harbored a second TBC1D24 variant (PMID: 27502353, 27281533); 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: 27281533, 31440721, 29100083, 33281559, 27502353, 34926809)
Genetic Services Laboratory, University of Chicago	RCV000189692	SCV000249121	uncertain significance	not specified	2014-08-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469036	SCV000549904	pathogenic	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 282 of the TBC1D24 protein (p.Pro282Arg). This variant is present in population databases (rs747538224, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal recessive epileptic encephalopathy (PMID: 27502353, 29100083; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 207505). 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000623272	SCV000741949	likely pathogenic	Inborn genetic diseases	2021-07-13	criteria provided, single submitter	clinical testing	The c.845C>G (p.P282R) alteration is located in exon 2 (coding exon 1) of the TBC1D24 gene. This alteration results from a C to G substitution at nucleotide position 845, causing the proline (P) at amino acid position 282 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD), the TBC1D24 c.845C>G alteration was observed in 0.02% (46/280780) of total alleles studied, with a frequency of 0.13% (45/35374) in the Latino subpopulation. This variant has been reported in the compound heterozygous state in three individuals with epilepsy (Appavu, 2016; Balestrini, 2016; Hamdan, 2017). The in silico prediction for the p.P282R alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV001330478	SCV001522162	pathogenic	DOORS syndrome	2019-10-22	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000254691	SCV004238751	likely pathogenic	not provided	2023-05-12	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678853	SCV000805044	uncertain significance	developmental delay with seizures	2016-08-15	no assertion criteria provided	clinical testing
Clinical Genomics Laboratory, Stanford Medicine	RCV000254691	SCV001427226	pathogenic	not provided	2020-03-02	no assertion criteria provided	clinical testing	The p.Pro282Arg variant in the TBC1D24 gene has been previously reported in at least 17 unrelated individuals with seizures and developmental delay, and co-segregated with disease in at least 3 affected relatives from 3 families (Appavu et al., 2016; GeneDx, personal communication, March 2, 2020; Hamdan et al., 2017; Invitae, personal communication, February 12, 2020). All affected individuals were homozygous or compound heterozygous. This variant was determined to be in trans with at least 4 different likely pathogenic or pathogenic variants consistent with autosomal recessive inheritance (GeneDx, personal communication, March 2, 2020; Hamdan et al., 2017; Invitae, personal communication, February 12, 2020). The presence of this variant with a diseaseassociated variant on the opposite allele increases suspicion for its pathogenicity. The p.Pro282Arg variant has also been identified in 45/35,374 Latino chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Pro282Arg variant as pathogenic for autosomal recessive TBC1D24-associated disorders based on the information above. [ACMG evidence codes used: PM2; PM3_verystrong; PP1_moderate; PP3]