LRRC10

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: ClinGen

LRRC10 was evaluated for autosomal recessive dilated cardiomyopathy (DCM). LRRC10 was originally evaluated for DCM by the ClinGen DCM GCEP on March 20, 2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on August 9, 2024. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. There is a lack of robust human genetic evidence demonstrating this gene-disease relationship in the literature at the time of curation. Two publications were reviewed in regards to human genetic evidence, but neither was felt to meet the threshold for scoring. The variant reported by Woon et al. 2018 (PMID: 29431102) has subsequently been found at a frequency higher than would be expected for a monogenic, pathogenic effect in population reference data sets. The second publication that presented genetic evidence was excluded due to DCM GCEP concerns of suspect data (Qu et al, 2015, PMID 26017719). This gene-disease assertion is supported by animal models, expression studies, and protein interaction studies. LRRC10 expression in the heart has been demonstrated in both mice and zebrafish (Kim et al, 2007, PMID: 17626279; Kim et al, 2007, PMID: 17601532; Brody et al, 2013, PMID: 23751912). Protein interaction studies demonstrate interaction with ACTC1, GATA4, and NKX2-5 (Brody et al 2012, PMID: 23236519; Brody et al, 2013, PMID: 23751912; Brody et al, 2016, PMID: 26608339). Knockout LRRC10 animal models have been shown to develop dilated cardiomyopathy and heart failure (Brody et al 2012, PMID: 23236519; Kim et al, 2007, PMID: 17601532; Brody et al, 2013, PMID: 23751912). However, the DCM GCEP elected to reduce the points awarded for animal models given the mode of inheritance has not been confirmed in any human genetic evidence data and a knockout model is a severe genetic manipulation. Overall, no convincing evidence for a causal role for LRRC10 and autosomal recessive DCM has been reported. Although this gene-disease assertion is supported by animal models, expression studies, and protein interaction studies, no reports have directly implicated the gene in humans. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on August 9, 2024 (SOP Version 10).