RANGRF

Inheritance Pattern: Unknown

Disease ID:MONDO:0015263

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: ClinGen

RANGRF encodes the MOG1 protein, a binding partner of Nav1.5 (encoded by SCN5A). MOG1 is proposed to act as a chaperone protein and regulate the surface expression of Nav1.5 (PMID:18184654, PMID: 35675436) - a protein with a well established causal relationship with Brugada syndrome. Due to its functional interaction with Nav1.5, RANGRF was initially investigated in relation to autosomal dominant Brugada syndrome in 2011 (Kattygnarath et al. PMID:21447824). However, the high allele frequency of loss-of-function polymorphisms suggests that RANGRF haploinsufficiency is not an autosomal dominant cause of Brugada syndrome. For example, the loss-of-function p.Glu61Ter polymorphism (PMIDs: 22010171, 21621375, 24142675) is too common to be an autosomal dominant cause of Brugada syndrome (allele frequency = 4.49 x 10-3, 29 homozygotes, gnomAD v4.1). Further, RANGRF is highly tolerant to loss-of-function variation (pLI = 0, LOEUF = 1.107, gnomAD v 4.1). The clinical genetics evidence in support of RANGRF being a monogenic cause of autosomal dominant Brugada syndrome thus rests on a cohort study from 2011, which proposes a dominant-negative mechanism. Kattygnarath et al. reported a RANGRF variant (c.249G>C, p.Glu83Asp) in a 41-year-old female who experienced a sudden cardiac arrest with suspected Brugada syndrome (PMID:21447824). Functional work was performed to assess the effect of this variant. Overexpression of RANGRF in HEK293 cells was observed to increase sodium current density, whereas overexpression of the p.Glu83Asp variant alone or in combination with the wild type protein did not. Further, rat cardiomyocytes transfected with the p.Glu83Asp variant displayed decreased Nav1.5 localisation around cell membrane regions relative to RANGRF wild-type cardiomyocytes. This study has subsequently been criticized on the basis that the presented ECGs were not diagnostic of Brugada syndrome and doubts have been raised as to the inference of a dominant-negative mechanism from the experimental data presented (PMID: 22010171). The p.Glu83Asp variant also has a relatively high population allele frequency (4.71 x 10-5, gnomAD v4.1). There are further experimental data in support of the physical interaction between the MOG1 protein and Nav1.5 and a potential role in Nav1.5 trafficking (PMID: 30282806, PMID: 35675436). Notably, a gene therapy has recently been developed, which is reported to upregulate RANGRF and increase cell surface Nav1.5 expression in a mouse model of SCN5A-mediated Brugada syndrome (PMID: 35675436). However, this mechanism is complicated by the observation that homozygous RANGRF knockout in mice does not affect Nav1.5 expression, localisation or activity in vivo, although cardiac features were observed (PMID: 35533905). Despite the emerging experimental insights, no further variants in RANGRF have been reported in association with Brugada syndrome since the previous ClinGen disputed classification was issued in 2017. The published experimental data alludes to a possible role for RANGRF variants in modifying cardiac disease risk by modulating Nav1.5 trafficking to the cell membrane. However, there is an absence of clinical genetic evidence to support an autosomal dominant mechanism of disease. Indeed, the high allele frequency of loss-of-function RANGRF variants renders this proposed mechanism doubtful. RANGRF was originally classified as disputed for Brugada syndrome by the ClinGen Brugada Syndrome Gene Curation Expert Panel in 2017. This gene-disease relationship was re-evaluated on 28 October, 2025, by the Hereditary Cardiovascular Disorders GCEP. Based on the passage of time, the total absence of new clinical genetic data and the publication of conflicting opinions, this gene-disease relationship has been classified as refuted. This classification was approved by the ClinGen HCVD GCEP on 28 October, 2025 (in accordance with SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: Ambry Genetics