rs71180793 — OBSCN OBSCN c.23838del

Frameshift deletion in obscurin, a giant sarcomeric scaffold protein; heterozygous carriers have a moderately elevated risk of OBSCN-related cardiomyopathy, warranting cardiac surveillance.

See your personal result for OBSCN

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

OBSCN — When the Sarcomere's Scaffold Carries a Frameshift

Obscurin is one of the largest proteins in the human body — a giant cytoskeletal scaffold encoded by the OBSCN gene on chromosome 1q42. In cardiac and skeletal muscle, obscurin anchors the sarcoplasmic reticulum to the sarcomere11 obscurin anchors the sarcoplasmic reticulum to the sarcomere
The protein integrates structural and signalling functions at the M-band of the sarcomere, coordinates myofibrillogenesis, and regulates calcium cycling during contraction and relaxation. The rs71180793 variant is a single-nucleotide deletion (c.23838del) that shifts the reading frame in the OBSCN coding sequence, creating a premature stop and truncating the obscurin protein at around serine-7947 (isoform C numbering). Whether this frameshift is sufficient alone to cause cardiomyopathy remains contested — ClinVar records conflicting interpretations ranging from benign to uncertain significance — but a growing body of evidence links OBSCN protein-truncating variants as a class to cardiomyopathy risk, particularly in adults.

The Mechanism

The rs71180793 deletion removes one cytosine from a homopolymeric CCCCC run in exon coding sequence, causing a frameshift at p.Ser794722 frameshift at p.Ser7947
The exact amino acid position varies by isoform; p.Ser6990fs in isoform b. The truncated protein loses obscurin's C-terminal kinase domains and the titin-binding SK3 domain, which are critical for sarcoplasmic reticulum organization and RhoGEF signalling. Mechanistically, the likely disease model is haploinsufficiency33 haploinsufficiency
One functional copy produces insufficient obscurin protein to maintain normal sarcomere architecture: truncating mutations reduce total obscurin immunoreactive material to 45–72% of normal in explanted DCM hearts. This partial depletion may disrupt SR anchorage and calcium handling, increasing arrhythmia susceptibility. Murine obscurin-knockout models confirm the downstream consequences: hearts lacking obscurin show larger ventricular volumes, reduced fractional shortening, impaired beta-adrenergic response, and increased ventricular tachycardia inducibility44 hearts lacking obscurin show larger ventricular volumes, reduced fractional shortening, impaired beta-adrenergic response, and increased ventricular tachycardia inducibility
Knockout model; end-diastolic volume increased 20%.

The Evidence

Evidence for OBSCN truncating variants as a cardiac risk class is accumulating, though the evidence for rs71180793 specifically remains emerging. In the largest study to date, Wu et al. 2021 performed whole-exome sequencing on 986 HCM patients and 761 controls55 Wu et al. 2021 performed whole-exome sequencing on 986 HCM patients and 761 controls
Replication cohort: 529 HCM patients and 307 controls; combined OR 3.58 and identified 28 qualifying OBSCN truncating variants in 2.6% of HCM patients versus 0.8% of controls (combined OR 3.58, p<0.001). Carriers had significantly worse outcomes over a mean 3.3-year follow-up: adjusted HR 3.1 (95% CI 1.40–6.70) for cardiovascular death and 2.63 (95% CI 1.21–5.71) for all-cause mortality. A separate proteomic study of explanted DCM hearts66 explanted DCM hearts
30 patients with familial DCM; whole-exon sequencing of 58 disease genes identified five OBSCN mutations in four samples, with haploinsufficient protein expression in all three assayed samples. The Genomics England cohort analysis77 Genomics England cohort analysis
926 adult cardiomyopathy patients independently confirmed that OBSCN was among the top mutated genes in adult DCM, enriched for protein-truncating variants.

The picture is more nuanced for rs71180793 itself. ClinVar lists three submissions with conflicting results: one benign call (Labcorp Genetics), one uncertain significance (Greenwood Genetic Center), and one likely benign (CeGaT). A separate submission from PreventionGenetics classifies it as likely benign for OBSCN-related disorder. The global deletion allele frequency of approximately 0.36% (gnomAD exomes) places it above the typical threshold for high-penetrance dominant cardiomyopathy genes. This variant likely has incomplete penetrance, or operates as a low-effect risk allele requiring additional genetic or environmental co-factors. Bi-allelic (homozygous) carriers are essentially absent in population databases, consistent with severe disease or embryonic lethality; heterozygous carrier status is the clinically relevant state.

Practical Implications

Given the conflicting ClinVar evidence and the emerging-to-moderate population data on OBSCN truncating variants as a class, rs71180793 heterozygous carriers warrant a measured response: not alarm, but not dismissal. Cardiac echocardiography can rule out subclinical cardiomyopathy; an ECG or Holter monitor can assess for arrhythmia burden. Decisions about intensity of follow-up should factor in personal and family history of cardiomyopathy, arrhythmia, or unexplained syncope. Carriers who participate in high-intensity competitive sport may wish to discuss pre-participation cardiac screening with a sports cardiologist.

Interactions

OBSCN truncating variants may compound with pathogenic variants in other sarcomere genes — particularly titin (TTN) and desmoplakin (DSP)88 titin (TTN) and desmoplakin (DSP)
Both identified alongside OBSCN mutations in DCM explant cohorts — to produce more severe phenotypes. OBSCN's titin-binding domain positions it in the same structural circuit as TTN, and co-occurrence of truncating variants in both genes may produce additive haploinsufficiency beyond what either alone causes. No formal compound action data exist for rs71180793 specifically, but clinicians evaluating OBSCN carriers for cardiomyopathy risk should consider comprehensive sarcomere gene panel testing.

Genotype Interpretations

What each possible genotype means for this variant.

II Non-Carrier Normal

No OBSCN frameshift deletion detected

You carry two intact copies of the OBSCN gene at this locus, with no deletion detected. This is the common genotype, found in approximately 99.3% of people globally. You do not carry the rs71180793 frameshift deletion and have no elevated genetic risk from this variant for OBSCN-related cardiomyopathy. Standard cardiac health practices apply.

DI Carrier Carrier

Heterozygous carrier of an OBSCN frameshift deletion

The rs71180793 deletion removes one cytosine from an OBSCN homopolymeric run, causing a frameshift at p.Ser7947 that truncates the obscurin protein and deletes its C-terminal kinase and titin-binding domains. OBSCN truncating variants as a class were enriched 3.6-fold in HCM patients versus controls in a whole-exome study of 986 patients (Wu et al. 2021, PMID 34601892), and carriers had adjusted hazard ratios of 2.6–3.1 for all-cause and cardiovascular mortality over ~3 years of follow-up. Animal models of obscurin deficiency show compensated DCM, impaired beta-adrenergic response, and increased arrhythmia inducibility (Pioner et al. 2025, PMID 40366302).

However, rs71180793 specifically has three ClinVar submissions with conflicting results (benign, uncertain significance, likely benign), and its allele frequency (~0.36% globally) is higher than typical high-penetrance dominant cardiomyopathy alleles. This places it in a gray zone between a low-penetrance risk variant and a benign polymorphism. Family history of cardiomyopathy, arrhythmia, or sudden cardiac death substantially increases the clinical relevance of this finding.

DD Homozygous Homozygous

Homozygous for the OBSCN frameshift deletion — extremely rare

You carry two copies of the rs71180793 frameshift deletion, meaning both OBSCN alleles are disrupted by this variant. This genotype is essentially absent from large population databases — estimated frequency below 0.001% — and is not well-characterized in published literature. Homozygous loss of obscurin in animal models produces severe dilated cardiomyopathy and pronounced arrhythmia susceptibility. This genotype requires urgent cardiological evaluation. If this result appears on a consumer genomics report, confirm with clinical-grade sequencing before acting.