MYH3

Chr 17ADAR

myosin heavy chain 3

Also known as: CPSFS1A, CPSFS1B, CPSKF1A, CPSKF1B, DA2A, DA2B, DA2B3, DA8

NCBI Gene: 4621 ENSG00000109063 UniProt: P11055 OMIM: 160720

The MYH3 protein is a contractile protein that converts chemical energy into mechanical energy through ATP hydrolysis and is essential for muscle function. Mutations cause multiple arthrogryposis syndromes including Freeman-Sheldon syndrome, Sheldon-Hall syndrome, and contractures-pterygia-spondylocarpotarsal fusion syndrome through dominant-negative mechanisms. These conditions follow autosomal dominant inheritance, though autosomal recessive inheritance has also been reported.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.634 OMIM phenotypes

Clinical Summary— MYH3

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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

131 unique Pathogenic / Likely Pathogenic· 920 VUS of 1932 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?

0.63LOEUF

pLI 0.000

Z-score 4.70

OE 0.50 (0.40–0.63)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.74Z-score

OE missense 0.85 (0.80–0.90)

855 obs / 1011.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.40–0.63)

0≤0.351.4

Missense OE?0.85 (0.80–0.90)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 51 / 102.2Missense obs/exp: 855 / 1011.1Syn Z: -0.97

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongMYH3-related spondylocarpotarsal synostosis syndromeLOFAR

definitiveMYH3-related distal arthrogryposisOTHERAD

This gene — mechanism propensity

0.88top 5%

GOF

0.6540th %ile

LOF

0.2288th %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.

ClinVar Variant Classifications

1932 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic60

Likely Pathogenic71

VUS920

Likely Benign651

Benign124

Conflicting90

Pathogenic

Likely Pathogenic

920

VUS

651

Likely Benign

124

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	45	11	4	0	60
Likely Pathogenic	35	34	2	0	71
VUS	11	823	70	16	920
Likely Benign	1	22	263	365	651
Benign	0	3	105	16	124
Conflicting	—				90
Total	92	893	444	397	1,916

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap MYH3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →