AMPK Methods and Protocols

purebred Hampshire pigs (denoted RN
)[ 19] and the first

described naturally occurring humanγ3 mutation (Arg225Trp)

[20], both of which are associated with increased skeletal muscle

glycogen content.

Notably in the setting of growing awareness of the disease, not

all of thePRKAG2variants described necessarily robustly satisfy

contemporary proposed criteria for classification of Mendelian var-

iants as pathogenic [21]. Findings in favor of interpretation of a

variant as pathogenic include de novo mutations (with confirma-

tion of both maternity and paternity) in an individual with the

disease but no family history, well-defined functional in vitro

and/or in vivo studies indicative of a deleterious effect of the

Table 1
(continued)

Variant Onset

Number of families/

patients Key features Reference

p.Arg531Gly Pediatric Family of four VPE, short PR interval, SVT;

sinus node dysfunction and

conduction block

LVH absent; early onset,

persistent hypertension

[30]

p.Arg531Gln Neonatal Three patients

(separate families)

Massive biventricular

hypertrophy, short PR

interval, fetal bradycardia and

death by 3 months;

macroglossia, dysmorphic

kidneys, skeletal muscle

glycogenosis (2)

[26]

p.Ser548Pro Adult Single patient Severe sinus bradycardia

requiring pacemaker, mild-

moderate LVH

Muscle stiffness, raised plasma

creatine kinase and skeletal

muscle glycogenosis

[67, 80]

AFatrial fibrillation,AVatrioventricular,LVHleft ventricular hypertrophy,RBBBright bundle branch block,SCD
sudden cardiac death,SVTsupraventricular tachycardia,VPEventricular pre-excitation
p. refers to position numbering in relation to the first amino acid of the protein sequence in accordance with HGVS
recommendations on nomenclature [91]
Note 1: Variants—While the variants listed are those which have been reported to date in the published literature as causal
forPRKAG2cardiomyopathy, not all of these necessarily meet current standards for interpretation of a sequence variant
as pathogenic or even likely pathogenic [21]. In particular, nonrecurrent variants reported as pathogenic should be
interpreted with care in the context of broader genetic evidence, including publically available datasets on variant
frequency (e.g., gnomAD [22], http://gnomad.broadinstitute.org/))
Note 2: Number of families/patients—In some cases, particularly with more frequently described variants, some overlap
may exist in reporting of individual cases

586 Arash Yavari et al.