Submissions for variant NM_001199107.2(TBC1D24):c.321T>A (p.Asn107Lys)

dbSNP: rs1057524192

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000418994	SCV000534817	likely pathogenic	not provided	2024-07-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31257224, 27502353, 35350397)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049900	SCV001213974	likely pathogenic	Developmental and epileptic encephalopathy, 1; Autosomal dominant nonsyndromic hearing loss 65; Caused by mutation in the TBC1 domain family, member 24	2023-06-10	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 107 of the TBC1D24 protein (p.Asn107Lys). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 not expected to disrupt TBC1D24 protein function. ClinVar contains an entry for this variant (Variation ID: 391688). This missense change has been observed in individual(s) with autosomal recessive TBC1D24-related epilepsy (PMID: 27502353). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993963	SCV004813818	likely pathogenic	TBC1D24-related disorder	2024-02-20	criteria provided, single submitter	clinical testing	Variant summary: TBC1D24 c.321T>A (p.Asn107Lys) results in a non-conservative amino acid change located in the Rab-GAP-TBC domain (IPR000195) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246174 control chromosomes. c.321T>A has been reported in trans along with a pathogenic nonsense variant in the literature in at-least two unrelated Navajo individuals affected with TBC1D24-Related Disorders (Appavu_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27502353). ClinVar contains an entry for this variant (Variation ID: 391688). Based on the evidence outlined above, the variant was classified as likely pathogenic.