Submissions for variant NM_001199107.2(TBC1D24):c.439G>A (p.Asp147Asn)

gnomAD frequency: 0.00009  dbSNP: rs267607103

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221106	SCV000272473	uncertain significance	not specified	2016-01-12	criteria provided, single submitter	clinical testing	The p.Asp147Asn variant in TBC1D24 has not been previously reported in individua ls with hearing loss. This variant has been identified in 0.1% (12/8488) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs267607103). Although this variant has been seen in the gen eral population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that the p.Asp 147Asn variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of th e p.Asp147Asn variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690744	SCV000818445	uncertain significance	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2024-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 147 of the TBC1D24 protein (p.Asp147Asn). This variant is present in population databases (rs267607103, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with TBC1D24-related conditions. ClinVar contains an entry for this variant (Variation ID: 229287). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TBC1D24 protein function with a negative predictive value of 80%. This variant disrupts the p.Asp147 amino acid residue in TBC1D24. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20727515). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001120423	SCV001278907	uncertain significance	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV001843495	SCV002103079	uncertain significance	not provided	2022-02-09	criteria provided, single submitter	clinical testing	PM5_supporting
GeneDx	RCV001843495	SCV002513206	uncertain significance	not provided	2022-04-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002503862	SCV002816293	uncertain significance	Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer's cramp syndrome; DOORS syndrome; Familial infantile myoclonic epilepsy; Autosomal recessive nonsyndromic hearing loss 86; Developmental and epileptic encephalopathy, 16; Autosomal dominant nonsyndromic hearing loss 65	2021-09-09	criteria provided, single submitter	clinical testing