TMEM168

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: ClinGen

The relationship between TMEM168 and autosomal dominant Brugada syndrome was suggested by Shimizu et al. in 2020, following the identification of the TMEM168 c.1616G>A, p.Arg539Gln variant in a family with Brugada syndrome (PMID: 32175648). Functional evidence from mouse and cell models suggested a mechanism involving decreased cardiomyocyte cell surface Nav1.5 expression in cells with the p.Arg539Gln variant. In a follow-up publication, Nguyen et al. suggested that the TMEM168 p.Arg539Gln variant was involved in sequestering αB-crystallin, thereby promoting Nav1.5 degradation (PMID: 34086898). However, with an allele frequency of 9.88 x 10-5 in the South Asian population (and 1.24 x 10-5 overall in gnomAD v4.1) this variant is too common to be a monogenic driver of autosomal dominant Brugada syndrome. As of the date of this classification, there are no further reports of TMEM168 variants causing cardiac disease in the literature. This gene-disease relationship was evaluated on January 13, 2026, by the Hereditary Cardiovascular Disorders GCEP. Given the absence of compelling clinical genetic data, this gene-disease classification was disputed. This classification was approved by the ClinGen Hereditary Cardiovascular Disorders GCEP on January 13, 2026 (in accordance with SOP Version 11).