Submissions for variant NM_001199107.2(TBC1D24):c.920A>G (p.Asn307Ser)

gnomAD frequency: 0.00001  dbSNP: rs761934676

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000707641	SCV000836743	uncertain significance	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2023-06-30	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 307 of the TBC1D24 protein (p.Asn307Ser). 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. 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) performed at Invitae indicates that this missense variant is expected to disrupt TBC1D24 protein function. ClinVar contains an entry for this variant (Variation ID: 583333). This variant has not been reported in the literature in individuals affected with TBC1D24-related conditions. This variant is present in population databases (rs761934676, gnomAD 0.0009%).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195523	SCV001365901	uncertain significance	not specified	2020-03-11	criteria provided, single submitter	clinical testing	The p.Asn307Ser variant in TBC1D24 has not been previously reported in individuals with hearing loss but has been identified in 1/111448 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 583333). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270076	SCV001448857	uncertain significance	Seizure; Nystagmus; Dysarthria; Myoclonus; Tremor	2019-10-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004547878	SCV004120241	likely pathogenic	TBC1D24-related disorder	2023-07-19	criteria provided, single submitter	clinical testing	The TBC1D24 c.920A>G variant is predicted to result in the amino acid substitution p.Asn307Ser. This variant was reported to be significantly enriched in individuals with age-related hearing loss in large GWAS studies. A more recent GWAS study showed the odds ratio was more than 4, suggesting a strong association (described as rs761934676, OR=6.59, p=5.9×10-13 in Ivarsdottir et al. 2021. PubMed ID: 34108613; OR=4.14, p=5.10E−09 in Praveen et al. 2022. PubMed ID: 35661827). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2547069-A-G). Two different missense substitutions affecting the same amino acid have been reported: p.Asn307His segregated in two large families with autosomal dominant non-syndromic hearing loss (Parzefall et al 2020. PubMed ID: 33281559) and p.Asn307Asp was compound heterozygous in two siblings with TBC1D24-related epilepsy (Appavu et al 2016. PubMed ID: 27502353). Taken together, we interpret this variant as likely pathogenic.