MYH7

Chr 14ADDigenic dominantAR

myosin heavy chain 7

Also known as: CMD1S, CMH1, CMYO7A, CMYO7B, CMYP7A, CMYP7B, MPD1, MYHCB

NCBI Gene: 4625 ENSG00000092054 UniProt: P12883 OMIM: 160760

The protein encodes the beta heavy chain subunit of cardiac myosin, which determines contractile velocity in cardiac muscle and is expressed in ventricular myocardium and slow-twitch skeletal muscle fibers. Mutations cause familial hypertrophic cardiomyopathy, dilated cardiomyopathy, left ventricular noncompaction, myosin storage myopathy, and Laing distal myopathy through dominant-negative mechanisms. Inheritance is primarily autosomal dominant, though autosomal recessive and digenic forms occur.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismAD/Digenic dominant/ARLOEUF 0.576 OMIM phenotypes

Clinical Summary— MYH7

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Gene-Disease Validity (ClinGen)

arrhythmogenic right ventricular cardiomyopathy · ADLimited

Limited evidence — not for standalone diagnostic reporting

5 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint

0.57LOEUF

pLI 0.000

Z-score 5.05

OE 0.45 (0.35–0.57)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

3.93Z-score

OE missense 0.67 (0.63–0.71)

742 obs / 1110.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.45 (0.35–0.57)

0≤0.351.4

Missense OE0.67 (0.63–0.71)

0≤0.61.4

Synonymous OE1.17

0≤1.21.6

LoF obs/exp: 43 / 96.5Missense obs/exp: 742 / 1110.9Syn Z: -2.91

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedMYH7-related arrhythmogenic right ventricular cardiomyopathyOTHERAD

definitiveMYH7-related hypertrophic cardiomyopathyOTHERAD

definitiveMYH7-related dilated cardiomyopathyOTHERAD

0.87top 5%

GOF

0.6639th %ile

LOF

0.2484th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNRegardless of the exact mutation and its specific effect on actomyosin dynamics, the link between MYH7 mutation and HCM derives from mutant myosin protein that is expressed, stable, and exerts dominant-negative effects.PMID:8282798

LOFMost likely, MYH7 haploinsufficiency due to one LoF allele results in a clinical phenotype only in compound heterozygous form with a missense variant.PMID:30924982

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.