Submissions for variant NM_001199107.2(TBC1D24):c.641G>A (p.Arg214His)

gnomAD frequency: 0.00068  dbSNP: rs200324356

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000118580	SCV000152986	uncertain significance	not specified	2019-06-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000535912	SCV000243335	uncertain significance	not provided	2024-07-08	criteria provided, single submitter	clinical testing	Identified with a second TBC1D24 variant on the opposite allele (in trans) in siblings with nonsyndromic hearing loss in published literature; authors propose that the p.(R214H) variant may be hypomorphic, resulting in a milder phenotype (PMID: 26371875); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27259978, 22277662, 24848745, 29741288, 32987832, 28428906, 34426522, 32860223, 29358611, 28301460, 27281533, 34440452, 35580552, 26371875, 36374051, 33986365, 36515421, 36964972, 37811145)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000118580	SCV000272474	likely benign	not specified	2019-03-01	criteria provided, single submitter	clinical testing	The p.Arg214His variant in TBC1D24 is classified as likely benign due to its high allele frequency. Although it has been reported in trans with a likely pathogenic variant in two Morroccan probands with hearing loss (2/272 alleles), it was also identified at a similar frequency in a race matched control population (1%, 4/400 chromosomes; Bakhchane 2015). Furthermore, this variant has been reported in several populations by gnomAD with a total allele frequency of 0.1% (271/280420) and an allele frequency of 0.19% (58/30602) of South Asian chromosomes including 1 homozygote. ACMG/AMP criteria: BS1.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000118580	SCV000297066	uncertain significance	not specified	2015-09-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084019	SCV000654212	likely benign	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2024-01-27	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000661907	SCV000784228	uncertain significance	Developmental and epileptic encephalopathy, 1	2018-03-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002316323	SCV000851349	uncertain significance	Inborn genetic diseases	2018-03-22	criteria provided, single submitter	clinical testing	The p.R214H variant (also known as c.641G>A), located in coding exon 1 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 641. The arginine at codon 214 is replaced by histidine, an amino acid with highly similar properties. This variant was identified with another TBC1D24 variant in three families with non-syndromic hearing loss; the variant was suggested to act as a hypomorph (Bakhchane A et al. PLoS ONE, 2015 Sep;10:e0138072; Rehman AU et al. Oral Dis, 2017 Jul;23:551-558). This variant was also detected in a patient with neonatal seizures and pervasive developmental disorder; however, the patient also had a de novo KCNQ2 mutation (Della Mina E et al. Eur. J. Hum. Genet., 2015 Mar;23:354-62). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000770979	SCV000897964	uncertain significance	Autosomal recessive nonsyndromic hearing loss 86	2018-05-31	criteria provided, single submitter	clinical testing	This recessive variant was identified in two brothers diagnosed with profound bilateral hearing loss. Both patients harbour also a second variant (see below) in this gene in compound heterozygosity
Mendelics	RCV000535912	SCV001135082	benign	not provided	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000535912	SCV001146070	likely benign	not provided	2018-11-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000535912	SCV001150742	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	TBC1D24: BP4, BS1
Illumina Laboratory Services, Illumina	RCV001120426	SCV001278910	benign	Familial infantile myoclonic epilepsy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000770979	SCV005399197	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 86	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene (PMID: 27281533). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Only a single missense has been reported to cause autosomal dominant disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (269 heterozygotes, 1 homozygote). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (3 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif, (Rab-GTPase-TBC domain; PDB, NCBI). (N) 0705 - A comparable variant (p.Arg214Cys) has been previous reported as a VUS (ClinVar). (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as a VUS, likely benign and likely pathogenic (ClinVar, LOVD). All reports of this variant being benign are in relation to epilepsy studies (PMID: 24848745, PMID: 29358611), however, this variant has been called a hypomorphic allele, and disease causing within deafness patients (PMID: 26371875, PMID: 28951997). (N) 0901 - Strong evidence for segregation with disease. This variant has been shown to segregate in two families with hearing loss (PMID: 26371875). (P) 1007 - No published functional evidence has been identified for this variant. (N) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease (IGV). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign