MYPN

Chr 10ADAR

myopalladin

Also known as: CMD1DD, CMH22, CMYO24, CMYP24, MYOP, NEM11, RCM4

NCBI Gene: 84665 ENSG00000138347 OMIM: 608517

Myopalladin is a sarcomere component that tethers nebulin (in skeletal muscle) and nebulette (in cardiac muscle) to alpha-actinin at the Z-lines. Mutations cause various cardiomyopathies (dilated, restrictive, and hypertrophic) and congenital myopathy, with both autosomal dominant and autosomal recessive inheritance patterns. The gene is highly constrained against loss-of-function variants, indicating that complete loss of function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Striated muscle in vertebrates comprises large proteins which must be organized properly to contract efficiently. Z-lines in striated muscle are a sign of this organization, representing the ends of actin thin filaments, titin, nebulin or nebulette and accessory proteins required for structure and function. This gene encodes a protein which interacts with nebulin in skeletal muscle or nebulette in cardiac muscle and alpha-actinin. In addition, this gene product can interact with a protein with the I-band indicating it has a regulatory as well as structural function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.514 OMIM phenotypes

Clinical Summary— MYPN

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Gene-Disease Validity (ClinGen)

MYPN-related myopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

3 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

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.000

Z-score 4.65

OE 0.35 (0.25–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.13Z-score

OE missense 0.99 (0.93–1.05)

716 obs / 725.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.25–0.51)

0≤0.351.4

Missense OE?0.99 (0.93–1.05)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 21 / 59.8Missense obs/exp: 716 / 725.8Syn Z: -0.80

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedMYPN-related hypertrophic cardiomyopathyOTHERAD

limitedMYPN-related dilated cardiomyopathyOTHERAD

strongMYPN-related childhood-onset, slowly progressive nemaline myopathyLOFAR

This gene — mechanism propensity

0.7034th %ile

GOF

0.6736th %ile

LOF

0.4234th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-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

GOFprediction above median

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.

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