Submission Details

The OBSCN gene has been associated with hypertrophic cardiomyopathy (HCM) in 8 probands in 3 publications. Three unique heterozygous variants of unknown significance (1 missense, 2 frameshift) with no experimental evidence to support their pathogenicity have been reported in humans (Xu et al, 2015, PMID 26573135). OBSCN was first associated with this disease in humans in 2007 (Arimura et al, PMID 17716621. However, the frequencies of the variants reported in this publication and a variant reported in 2014 (Girolami et al, PMID 25173926) in the ExAC database (exac.broadinstitute.org) are consistent with benign variation. Three additional variants found in 3 unrelated probands in Xu et al, 2015 (PMID 26573135) were also excluded as causative after expert review. Additional cases reviewed during recuration in 2022, revealed another null variant found via NGS in Forleo et al, 2017 (PMID: 28750076). Here, the proband also displayed a truncating variant in MYBPC3, a gene known to be linked to HCM. This likely excludes the OBSCN variant as causative without further segregation or mechanical evidence. New case-control evidence (Wu et al, 2021, PMID 34601892) on OBSCN in HCM showed statistical enrichment in cases compared to controls. However, there were limitations including affected individuals having known pathogenic variants in other genes associated with HCM. Of note, a knock-in mouse model with R4344Q homozygous mice display various symptoms such as arrhythmia, tachycardia, and PVCs. Additional studies have continued to investigate the pathogenicity of R344Q, but no experimental evidence has clearly supported pathogenicity for this variant in regards to hypertrophic cardiomyopathy (Hu et al, 2020, PMID 32528308; Fukuzawa et al, 2021, PMID 33438037; Hu et al, 2017, PMID 630914). Given this variant's high frequency in gnomAD (0.09%) with over 100 homozygous individuals reported, the pathogenicity of this variant remains unclear. However, this variant's high gnomAD frequency of 0.09716 in the African population excludes it from pathogenic consideration.The mechanism for disease is unknown. The gene-disease association is supported by expression data in addition to an in vitro assay. In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was originally approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on February 1, 2017. This gene-disease relationship was reevaluated on April 13, 2022 by the Hereditary Cardiovascular Disorders GCEP. As a result of this reevaluation, the classification did not change.