Submissions for variant NM_001199107.2(TBC1D24):c.1327G>A (p.Glu443Lys)

gnomAD frequency: 0.00163  dbSNP: rs141399869

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000190450	SCV000245329	uncertain significance	not specified	2017-09-22	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TBC1D24 gene. The E443K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E443K variant is observed in 34/5,298 (0.6%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E443K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Eurofins Ntd Llc (ga)	RCV000726025	SCV000341315	uncertain significance	not provided	2017-12-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079461	SCV000560546	likely benign	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2025-01-27	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000190450	SCV000597396	uncertain significance	not specified	2015-09-18	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000190450	SCV000711547	benign	not specified	2014-11-24	criteria provided, single submitter	clinical testing	Glu443Lys in exon 7 of TBC1D24: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (22/4106) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs141399869).
Ambry Genetics	RCV002317666	SCV000851038	uncertain significance	Inborn genetic diseases	2018-12-18	criteria provided, single submitter	clinical testing	The p.E443K variant (also known as c.1327G>A), located in coding exon 6 of the TBC1D24 gene, results from a G to A substitution at nucleotide position 1327. The glutamic acid at codon 443 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002054246	SCV002495980	uncertain significance	DOORS syndrome; Familial infantile myoclonic epilepsy; Autosomal recessive nonsyndromic hearing loss 86; Developmental and epileptic encephalopathy, 16; Autosomal dominant nonsyndromic hearing loss 65	2022-02-03	criteria provided, single submitter	clinical testing	TBC1D24 NM_001199107.1 exon 7 p.Glu443Lys (c.1327G>A): This variant has not been reported in the literature but is present in 0.5% (215/41420) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-2500292-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:208413). Evolutionary conservation for this variant is limited or unavailable; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000190450	SCV004037883	uncertain significance	not specified	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: TBC1D24 c.1327G>A (p.Glu443Lys) results in a conservative amino acid change located in the TLDc domain (IPR006571) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 233640 control chromosomes. This frequency does not allow any conclusion about variant significance. To our knowledge, no occurrence of c.1327G>A in individuals affected with TBC1D24-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Five classified the variant as uncertain significance, and one classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.