MYH8

Chr 17AD

myosin heavy chain 8

Also known as: DA7, MyHC-peri, MyHC-pn, gtMHC-F

NCBI Gene: 4626 ENSG00000133020 UniProt: P13535 OMIM: 160741

The MYH8 protein is a myosin heavy chain that functions in skeletal muscle contraction and is predominantly expressed in fetal skeletal muscle. Mutations cause trismus-pseudocamptodactyly syndrome and Carney complex variant, both inherited in an autosomal dominant pattern. The gene shows very low constraint against loss-of-function variants (pLI near zero), suggesting the pathogenic variants likely affect muscle function through other mechanisms.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is predominantly expressed in fetal skeletal muscle. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in trismus-pseudocamptodactyly syndrome. [provided by RefSeq, Sep 2009]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 1.032 OMIM phenotypes

Clinical Summary— MYH8

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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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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 349 VUS of 514 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.03LOEUF

pLI 0.000

Z-score 1.30

OE 0.86 (0.72–1.03)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.35Z-score

OE missense 0.97 (0.92–1.02)

965 obs / 996.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.86 (0.72–1.03)

0≤0.351.4

Missense OE?0.97 (0.92–1.02)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 86 / 100.0Missense obs/exp: 965 / 996.0Syn Z: -0.68

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedMYH8-related Carney complex variantOTHERAD

strongMYH8-related Trismus-pseudocamptodactyly syndromeLOFAD

This gene — mechanism propensity

0.82top 10%

GOF

0.6151th %ile

LOF

0.3358th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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.

ClinVar Variant Classifications

514 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic2

VUS349

Likely Benign71

Benign58

Conflicting30

Pathogenic

Likely Pathogenic

349

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	2	0	0	0	2
VUS	17	297	15	20	349
Likely Benign	1	17	27	26	71
Benign	0	6	36	16	58
Conflicting	—				30
Total	20	321	78	62	511

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

12 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap MYH8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →