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This summary evaluates the association between TMC4 (HGNC:22998) and metabolic dysfunction-associated steatotic liver disease (MONDO:0013209). Multiple studies have assessed the role of the rs641738 variant in TMC4, initially identifying a missense change that leads to a p.Gly17Glu substitution. Early reports, including a large-scale analysis from Gastroenterology, suggested that this variant may contribute to disease risk in European populations (PMID:26850495). The variant has been denoted in HGVS notation as c.49G>A (p.Gly17Glu), complying with rigorous three-letter amino acid codes and formatting requirements.
However, subsequent work published in Scientific Reports reported no significant association between the TMC4 missense variant and nonalcoholic fatty liver disease, despite adequate statistical power in the case–control design (PMID:29572551). This conflicting genetic evidence raises concerns about the independent pathogenic role of TMC4 in the metabolic dysfunction-associated steatotic liver disease phenotype.
Beyond case–control analyses, broader multi-patient studies and genome-wide association meta-analyses have included the TMC4 locus among several lipid metabolism–related regions. Yet, these studies highlight that the functional mechanistic data largely support alterations in MBOAT7 rather than TMC4, suggesting that the risk may be conferred by nearby or interacting loci rather than by TMC4 alone. In particular, functional assessments indicate that changes in hepatic lipid remodeling and expression profiles are predominantly related to MBOAT7 activity (PMID:31621579).
The genetic evidence for TMC4 is further confounded by the absence of clear segregation data or a substantial number of unrelated affected probands carrying the c.49G>A (p.Gly17Glu) variant. The lack of reproducible functional studies directly implicating TMC4 and the failure of some studies to validate an association reduce confidence in a causal link between TMC4 variation and disease onset.
In light of the conflicting results from both genetic and functional investigations, the overall strength of the TMC4–metabolic dysfunction-associated steatotic liver disease association is best classified as Disputed. The evidence does not reach the threshold for a definitive genetic effect, and it remains plausible that the reported association may emanate from neighboring genetic effects, particularly from MBOAT7.
Key take‑home: While initial reports suggested a contributory role for a TMC4 missense variant in disease susceptibility, subsequent conflicting data undermine its independent clinical utility, underscoring the need for additional, targeted studies.
Gene–Disease AssociationDisputedConflicting evidence exists: one study reported an association in a large European cohort (PMID:26850495), while another robust case–control study failed to validate this association (PMID:29572551). Genetic EvidenceLimitedA single missense variant, c.49G>A (p.Gly17Glu), has been reported in association analyses; however, inconsistencies across studies and insufficient segregation data limit its genetic evidence strength. Functional EvidenceLimitedFunctional studies largely point to alterations in MBOAT7-mediated lipid remodeling rather than a direct role for TMC4, undermining a clear mechanistic link between TMC4 variation and disease progression (PMID:31621579). |