Hypertrophic cardiomyopathy_HCM

Gene: MYLK2

Red List (low evidence)

LIMITED evidence by ClinGen HCM working group PMID: 30681346

Created: 21 Jun 2020, 6:37 a.m. | Last Modified: 21 Jun 2020, 6:37 a.m.

Panel Version: 0.67

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
HCM

Publications

• 30681346

Red List (low evidence)

Suggested to be either monoallelic or digenic inheritance, however very little evidence exists for gene-disease association.

ClinVar - LP/P: Frameshift(0), Missense(1), Nonsense(0), Splice site(0)
OMIM: only 1 pathogenic report from a 2001 paper (Davis, J. et al. (2001)) in a patient who had 2x MYLK2 missense on the maternal allele, and a paternally inherited MYH7 missense. These MYLK2 variants have since been classified as LB/B and VUS in ClinVar.
Decipher: 2x missense and 1x PTC B/LB/VUS/conflicting, only 1x LP missense left, with no evidence.
HGMD: only 3 papers with pathogenic variants reported (summarised below)
PMID: 11733062; Davis, J. et al. (2001): initial report of MYLK2 gene-disease association (as mentioned in OMIM). Functional study suggested a GoF for the double mutant, however evidence for pathogenicity and gene-disease association was very weak.
PMID: 24082139; Gonzalez-Garay, M. et al. (2013): a missense identified in 1x patient with familial HCM in supplementary table, no evidence for pathogenicity provided.
PMID: 25825456; Wang, L. et al. (2016): 1 family with 4 different missense variants (all in different genes – KCNQ1, MYH7 & TMEM70) the proband carried all 4, other affected family members carried 2 each. MYLK2 was maternally inherited with a KCNQ1 variant. All carriers of the MYLK2 variant showed inverted ECG T waves, however no further evidence for pathogenicity was provided.
PMID: 20301725; Gene Reviews: MYLK2 classified as limited evidence by ClinGen, inheritance is considered to be digenic.
PanelApp UK: grey, red & amber reviews; amber for HCM – limited evidence.

Created: 5 May 2020, 2:29 a.m. | Last Modified: 5 May 2020, 2:29 a.m.

Panel Version: 0.23

Mode of inheritance
Other

Phenotypes
Cardiomyopathy, hypertrophic, 1, digenic, 192600

Publications

• 11733062
• 24082139
• 25825456
• 20301725

Mode of pathogenicity
Other