Hypertrophic cardiomyopathy

Gene: MYL2

Green List (high evidence)

Comment on mode of inheritance: There are at least 5 unrelated families with biallelic MYL2 variants, and a fatal infantile-onset myocardial disease. The cardiomyopathy presentation was mixed, mostly dilated but also including features of hypertrophic, restrictive, and non-compation cardiomyopathy. Based on available evidence, the mode of inheritance should be updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 25 Feb 2026, 11:21 a.m. | Last Modified: 25 Feb 2026, 11:29 a.m.

Panel Version: 5.29

BIALLELIC CASES:
PMID: 33731536 Tamamitsu et al., 2021
Japanese girl, presented with infantile-onset skeletal myopathy and non-compaction cardiomyopathy at 4 months. She was compound het for MYL2 variants: c.431_432del, p.P144Rfs*57 and c.499T>C, p.*167Qext*?. Proband died at 12 months, elder sister similarly affected with same variants, deceased at 8 months.

PMID: 32453731 Manivannan et al., 2020
Patient with severe infantile onset HCM and mitral valve dysplasia, leading to death before 1 year of age. Proband was homozygous for a frameshift MYL2 variant: c.431_432delCT: p.Pro144Argfs*57;MYL2-fs - consanguineous parents were heterozygous & unaffected. History of multiple infant deaths in the family due to early-onset cardiac disease.

PMID: 31127036 Marttila et al., 2019
Patient with congenital fiber-type disproportion (CFTD) and fatal infantile cardiomyopathy. Individual was homozygous for MYL2 c.188del, p.(Asn63Metfs*7), and heterozygous for NEB:c.25435C>T, p.(Gln8479*) - inherited from his father. MYL2 variant was ultimately thought to explain the phenotype in full.

PMID: 23365102 Weterman et al., 2013
1. Group of 11 individuals from 8 Dutch families with cardioskeletal myopathy with onset and death in infancy, morphological features of muscle type I hypotrophy with myofibrillar disorganization and dilated cardiomyopathy. All affected individuals homozygous for MYL2 splice variant c.403-1G>C, heterozygous carriers unaffected. Founder variant suspected.
2. Two Italian siblings with compound heterozygous mutations, c.431delC, p.(Pro144LeufsX2) and c.432delT, p.(Asp145ThrfsX2) - both had infantile cardiomyopathy.
All individuals died within 6 months after birth. The cardiomyopathy was mixed, mostly dilated but also including features of hypertrophic, restrictive, and non-compation cardiomyopathy.

MYL2 is associated with AD Cardiomyopathy, hypertrophic, 10, MIM:608758 & AR Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, MIM:619424 (OMIM accessed 25th Feb 2026).

Created: 25 Feb 2026, 11:09 a.m. | Last Modified: 25 Feb 2026, 11:19 a.m.

Panel Version: 5.27

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, OMIM:619424; Cardiomyopathy, hypertrophic, 10, OMIM:608758

Publications

• 23365102
• 31127036
• 32453731
• 33731536

Green List (high evidence)

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.

Created: 2 Dec 2019, 11:26 a.m. | Last Modified: 2 Dec 2019, 11:26 a.m.

Panel Version: 1.81

Green List (high evidence)

Cardiomyopathy, hypertrophic, 10 (608758)

Created: 25 Mar 2019, 4:30 p.m.

Sarcomeric HCM genes - well established gene

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Gene on Royal Brompton diagnostic panel. Definitive HCM-causing sarcomeric gene.

Created: 19 Mar 2019, 5:19 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• 30681346

I don't know

This gene was part of an initial gene list collated by Matthew Edwards Royal Brompton Hospital sent 16th Jan 2019 on behalf of the London South GLH for review by the GMS Cardiology Specialist Group. Only gene symbol from the Royal Brompton gene panel was provided - suggested initial gene rating and evidence for inclusion not provided with the list.

Created: 20 Feb 2019, 2:17 p.m.

Green List (high evidence)

Gene currently tested on Manchester cardiac gene panel. 67 variants listed on HGMD (accessed 29/01/2019). ClinGen Knowledge Base: definitive association with hypertrophic cardiomyopathy 10 (accessed 29/01/2019).

Created: 14 Feb 2019, 1:38 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Cardiomyopathy, familial hypertrophic, 10 (608758)

Publications

• 28369730
• 27532257

Variants in this GENE are reported as part of current diagnostic practice

Comment when marking as ready: On Manchester HCM diagnostic panel

Created: 11 Feb 2016, 3:08 p.m.

Green List (high evidence)

Variants in this GENE are reported as part of current diagnostic practice