OBSCN

Inheritance Pattern: AR

Disease ID:MONDO:0005290

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0859371

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: ClinGen

OBSCN was originally evaluated for DCM by the ClinGen DCM GCEP on June 11 2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on February 7 2025. As a result, the classification is unchanged. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein: OBSCN was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2015 (Marston et al., 2015, PMID: 26406308). Human genetic evidence supporting this gene-disease relationship includes case-level data. Several variants (including missense and frameshift variants) have been reported in humans with DCM (Marston et al., 2015, PMID: 26406308; Rowland et al., 2015, PMID: 27855815); however, all but one (missense) variant are present in control populations at a frequency higher than expected for dominant DCM. The gene-disease assertion is supported by expression studies and in vitro functional assays. Expression studies have documented low levels of Obscurin within the heart (Young et al., 2001, PMID: 11448995; Marston et al., 2015, PMID: 26406308). Yeast 2 hybrid and in vitro binding assay noted an interaction between Obscurin and the titin Z-disc (Young et al., 2001, PMID: 11448995). In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of OBSCN with autosomal dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on February 7, 2025. (SOP Version 7).

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

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.