ClinVar Miner

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

gnomAD frequency: 0.00068  dbSNP: rs200324356
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Total submissions: 12
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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 2023-06-15 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 (Bakhchane et al., 2015); authors propose that the p.(R214H) variant may be hypomorphic, resulting in a milder phenotype; In silico analysis supports 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)
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
Invitae 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.

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