rs128627256 — DMD Arg2905Ter (R2905X)

Nonsense variant in dystrophin that eliminates full-length protein, causing X-linked dilated cardiomyopathy in males and significant carrier risk in females

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DMD Arg2905Ter — When the Heart Carries a Hidden Fault

Dystrophin11 Dystrophin
A 427 kDa cytoskeletal protein encoded by one of the largest genes in the human genome, spanning 2.4 Mb on the X chromosome. It forms a critical mechanical link between the intracellular actin cytoskeleton and the extracellular matrix in both skeletal and cardiac muscle. is the protein that keeps muscle fibres from tearing apart during every contraction. When full-length dystrophin is lost, the sarcolemma becomes fragile, membrane micro-ruptures accumulate with each heartbeat, and cardiomyocytes die faster than they can be replaced — culminating in dilated cardiomyopathy (DCM)22 dilated cardiomyopathy (DCM)
A form of heart failure in which the ventricles enlarge and weaken, reducing the heart's pumping capacity. In DMD-associated DCM, this is the direct result of dystrophin-deficient cardiomyocyte death..

The rs128627256 variant — NM_004006.3:c.8713C>T (p.Arg2905Ter) in the full-length muscle isoform Dp427m — converts an arginine codon to a premature stop codon in the last exon region of the dystrophin rod domain. It is classified as pathogenic in ClinVar (Variation 11288) and is associated with Duchenne muscular dystrophy, Becker muscular dystrophy, and dilated cardiomyopathy 3B (OMIM 302045) depending on the degree of residual protein produced and the specific isoforms affected.

The Mechanism

Full-length dystrophin (Dp427) is expressed in both skeletal and cardiac muscle. Shorter isoforms (Dp260, Dp140, Dp71) are expressed in the retina, brain, and other tissues. The p.Arg2905Ter nonsense mutation introduces a premature stop codon that triggers nonsense-mediated mRNA decay33 nonsense-mediated mRNA decay
A cellular quality-control pathway that degrades mRNAs containing premature stop codons, preventing production of truncated proteins that could be toxic. for the full-length isoforms, eliminating or severely reducing full-length dystrophin protein. Without dystrophin, the dystrophin-associated protein complex (DAPC) at the sarcolemma disassembles, leaving the muscle cell membrane unanchored and vulnerable to contraction-induced damage.

In the heart, this loss is insidious: cardiac cells do not regenerate the way skeletal muscle does, so each injury event is permanent. Over years to decades, cumulative cardiomyocyte loss leads to ventricular dilation, fibrosis, and progressive systolic dysfunction. Cardiomyopathy occurs in nearly all males with DMD after age 18, and heart failure from DCM is the most common cause of death in Becker muscular dystrophy44 heart failure from DCM is the most common cause of death in Becker muscular dystrophy
In BMD, skeletal muscle involvement is milder and patients survive longer, making the cardiac phenotype the dominant clinical problem. Mean age of death from cardiac causes is in the mid-40s..

The Evidence

GeneReviews Dystrophinopathies55 GeneReviews Dystrophinopathies
Darras et al., updated 2022 — PMID 20301298 synthesises decades of natural history data: cardiomyopathy affects approximately one-third of DMD males by age 14, one-half by age 18, and virtually all by adulthood. Complete cardiac evaluation is recommended at least every two years from diagnosis, with annual evaluations from approximately age 10.

For female carriers, the picture is more nuanced. A systematic review by Ishizaki et al. (2018) — PMID 2980175166 Ishizaki et al. (2018) — PMID 29801751 found dilated cardiomyopathy in 7.3–16.7% of female DMD carriers, with frequency increasing with age. A focused review by Lim et al. (2020) — PMID 3265040377 Lim et al. (2020) — PMID 32650403 placed the overall DCM rate at ~8% of female carriers, while noting heterogeneity driven by X-inactivation patterns: females with skewed X-inactivation (where the variant-bearing X is preferentially active) face substantially higher cardiac risk than those with balanced inactivation.

An analysis of adult-onset DCM cohorts by Johnson et al. (2023) — PMID 3767154988 Johnson et al. (2023) — PMID 37671549 found pathogenic DMD variants in 12.5% of unselected male DCM probands, with high rates of heart failure, transplantation, and ventricular arrhythmias — underscoring that DMD-associated DCM is not rare in adult cardiology practice, even when the neuromuscular diagnosis was never made.

Practical Actions

The cardiac risk from DMD variants is manageable with systematic early surveillance. In males with a confirmed DMD pathogenic variant, Bourke et al. (2022) — PMID 3625299299 Bourke et al. (2022) — PMID 36252992 recommend cardiac MRI in addition to echocardiography, with ACE inhibitors or angiotensin receptor blockers initiated when left ventricular ejection fraction (LVEF) falls below 55% (or sometimes prophylactically), and beta-blockers added when LVEF falls below 45%. Heart transplant and mechanical circulatory support are options for end-stage disease.

For female carriers, GeneReviews recommends1010 GeneReviews recommends a complete cardiac evaluation by a specialist in late adolescence or early adulthood, then every five years from age 25–30. Any new cardiorespiratory symptoms warrant earlier evaluation. Pregnancy increases cardiac demands and is a recognized trigger for decompensation in carrier females — obstetric teams should be aware of carrier status.

Genetic counseling is essential for the extended family. In X-linked inheritance, an affected male passes the variant to all daughters (who become obligate carriers) and no sons. A carrier female has a 50% chance of passing the variant to each son (who would be affected) and each daughter (who would become a carrier).

Interactions

No inter-SNP compound action is warranted for this variant. Cardiac risk in males depends primarily on the presence of any pathogenic DMD variant that abolishes full-length dystrophin, rather than on interactions with other common SNPs. In females, cardiac risk is modulated by X-inactivation status1111 X-inactivation status
The process by which one X chromosome is silenced in each cell of a female. If the variant-bearing X is disproportionately active (skewed X-inactivation), more cells produce defective dystrophin and cardiac risk rises substantially. but this is not captured by a second SNP — it requires X-inactivation assays. DMD gene variants that truncate different isoforms may show variable skeletal muscle severity, but cardiac involvement is broadly present across truncating variants.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier / Unaffected Normal

No Arg2905Ter variant — standard dystrophin function at this position

You carry the common reference allele at rs128627256. In males, this means no elevated risk for DMD-associated dilated cardiomyopathy from this specific variant. In females, GG indicates you are not a carrier of this pathogenic DMD variant. The vast majority of people worldwide share this genotype — the alternate allele is absent from large population databases including gnomAD. Note that other pathogenic DMD variants may be present if muscular dystrophy has been diagnosed in a family member through comprehensive sequencing.

AA Affected (Hemizygous Male / Homozygous Female) High Risk

Carries the DMD Arg2905Ter variant — high risk of dilated cardiomyopathy

The Arg2905Ter nonsense mutation eliminates full-length dystrophin (Dp427) by triggering premature termination of protein translation. Without full-length dystrophin, the dystrophin-associated protein complex disassembles at the sarcolemma, making muscle cell membranes mechanically fragile. In the heart, where cardiomyocytes cannot meaningfully regenerate, this leads to cumulative cell death, fibrosis, ventricular dilation, and progressive systolic dysfunction.

The cardiac and skeletal muscle phenotypes may diverge depending on which downstream dystrophin isoforms retain expression. Variants that affect only full-length Dp427 and preserve expression of Dp260, Dp140, and Dp71 isoforms may produce the "X-linked dilated cardiomyopathy" (XLCM) phenotype — severe cardiac involvement with relatively spared skeletal muscle — rather than classical Duchenne presentation. The Arg2905Ter variant disrupts multiple Dp427 isoforms but not all shorter isoforms, potentially explaining its association with both classic DMD and the XLCM phenotype in ClinVar.

First-line cardiac management includes ACE inhibitors or angiotensin receptor blockers (begun when LVEF falls below 55%, sometimes prophylactically from age 10), with beta-blockers added at LVEF < 45%. Cardiac MRI offers superior assessment of fibrosis and early dysfunction compared to echocardiography alone. Advanced therapies — heart transplantation, left ventricular assist devices — are options for end-stage disease in patients with preserved skeletal muscle function. Emerging dystrophin-restoration therapies (exon skipping, micro- dystrophin gene therapy) are active areas of clinical investigation and may have cardiac benefit as they advance.

AG Carrier Female Carrier

Carrier of the DMD Arg2905Ter variant — cardiac monitoring required

In female carriers of DMD pathogenic variants, the cardiac phenotype arises from X-inactivation mosaicism. Each cardiac cell independently silences one X chromosome early in development, creating a mosaic where some cells express normal dystrophin and others do not. When X-inactivation is balanced (~50/50), enough normal dystrophin is present to largely protect cardiac function. When inactivation is skewed toward the variant-bearing X, a higher fraction of cardiomyocytes are dystrophin-deficient, and the cumulative damage over decades leads to dilated cardiomyopathy.

The risk increases progressively with age, making continued surveillance important through adulthood. Pregnancy is a recognized period of elevated cardiac risk for carrier females, as increased cardiac demands can unmask subclinical dysfunction; obstetric care teams should be informed of carrier status. Management, when DCM develops, follows the same pharmacological pathway as other forms of DCM: ACE inhibitors/ARBs and beta-blockers are first-line, with more intensive intervention for progressive disease.