Dilated and arrhythmogenic cardiomyopathy

Gene: MYLK3

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The GLHs agree that current evidence is insufficient to support haploinsufficiency of MYLK3 as a robust disease mechanism for dilated cardiomyopathy (DCM), and that loss-of-function variants in this gene should not yet be treated as clearly diagnostic. The gene shows no strong population-level constraint for heterozygous loss of function and lacks adequately powered, peer_reviewed casecontrol data and pathogenic LoF precedent needed to meet published PVS1 criteria, so variants in MYLK3 should not presently be reported as a definitive cause of disease or used to guide clinical management with high confidence.

Created: 10 Dec 2025, 3:42 p.m. | Last Modified: 10 Dec 2025, 3:42 p.m.

Panel Version: 3.10

Green List (high evidence)

Several mouse models (and a zebrafish), one of which is heterozygous KO which recapitulates DCM (31244672). Good expression/protein interaction evidence 17885681, 18202317)

Rare cases in literature - PMID: 29235529 has two families: Family A - two early onset sibs and their affected mother (later onset) had heterozygous MYLK3 LOF variant - sibs also had a FLNC LOF variant (from unaffected father), likely explaining early onset. Family B two later onset sibs with heterozygous MYLK3 LOF variant. functional studies of both showed reduced protein expression. PMID: 30690923: has proband with heterozygous LOF variant. 3 consanguineous families with hom LOf (2 families) and hom missense (1 family).

We've seen 10 LOF variants in DCM patients (with 3 detected in control set of non-DCM cases ~5000 samples - one possibly too young for phenotype, 2 with variant in only one of two isforms expressed in heart), but currently classify as VUS due to limited haploinsufficiency evidence. (Clin~Gen curation still pending)

Created: 14 Jul 2025, 8:50 a.m. | Last Modified: 14 Jul 2025, 8:50 a.m.

Panel Version: 3.1

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Dilated Cardiomyopathy

Publications

• 17885681
• 31244672
• 37128901
• 32213617
• 29235529
• 30690923

I don't know

Tagged for GMS review to determine whether this gene should remain Amber or be promoted to Green. As stated by Matthew Edwards, the evidence is borderline - several unrelated cases and supportive mouse model but MOI varies, one family also had variants in another DCM gene and there are unaffected carriers. MYLK3 is green on the R135 Paediatric or syndromic cardiomyopathy panel based on the same evidence.

Created: 30 Jun 2025, 8:58 a.m. | Last Modified: 30 Jun 2025, 8:58 a.m.

Panel Version: 3.1

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber.

Created: 30 Jan 2023, 2:04 p.m. | Last Modified: 30 Jan 2023, 2:04 p.m.

Panel Version: 2.4

Green List (high evidence)

This gene is also on the Cardiomyopathies - including childhood onset (Version 1.35) as an Amber gene with a recommendation of promoting to Green. This gene is not associated with a phenotype on OMIM or Gene2Phenotype.

PMID: 29235529 describes 2 families with heterozygous variant in this gene. Family A - 2 sibs diagnosed with DCM at 9 and 10 months of age and affected mother diagnosed with DCM at 40 yo. As the children had a more severe phenotype and earlier onset than the mother the authors did further analysis and found the sibs had an additional variant in FLNC, which is also linked to DCM. The authors suggest this additional variant could account for the more severe phenotype in the children.

Family B - 2 brothers diagnosed with DCM at 56 and 52 yo, both have a heterozygous frameshift variant in this gene. Mother and sister had died young and DCM diagnosis is inconclusive.

PMID: 30690923 describes another case. Proband has a heterozygous frameshift variant in this gene. Rest of the family have no cardiac phenotype and no variants in this gene except for one daughter. Daughter has the same variant and has dilation of LV and ST-T abnormalities but these do not meet the criteria for DCM.

PMID: 32870709 describes three consanguineous families with homozygous variants in this gene.

Review from Zornitza Stark:
"Rating: I don't know

Two families reported with mono-allelic variants (one extension, one frameshift), and three consanguineous families reported with bi-allelic variants (two hmz frameshift, one hmz missense). Supportive mouse models.
Sources: Literature
Created: 16 Apr 2021, 9:24 a.m."

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Sources: Literature

Created: 20 Apr 2021, 10:22 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Dilated cardiomyopathy, MONDO:0005021

Publications

• 29235529
• 31244672
• 32213617
• 32870709
• 30690923