Gene	SCN5A
OMIM gene number	600163
Disease name	SCN5A-related long QT Syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Inheritance	Autosomal dominant
Allelic requirement	Monoallelic autosomal
Inheritance qualifiers	Typified by incomplete penetrance
Disease-associated variant consequence	Altered gene product sequence
Variant classes reported with evidence of pathogenicity	Missense; inframe insertion; inframe deletion
Potential novel variant classes based on predicted functional consequence	splice_acceptor_variant_NMD_escaping; splice_donor_variant_NMD_escaping; splice_donor_variant; frameshift_variant_NMD_escaping; stop_gained_NMD_escaping; stop_lost
Narrative summary Altered gene product sequence of SCN5A causes long QT syndrome. The likely disease mechanism is gain of function. Over 200 pathogenic missense variants and in-frame deletions or insertions have been reported. It is thought that gain-of-function SCN5A pathogenic variants lead to enhanced sodium current, which can trigger life-threating arrhythmias. Rare missense variants are estimated to occur in around 2% of healthy White and 5% of healthy non-White subjects so collectively missense variants are not rare in the healthy population. It has been noted that approximately 10% of genotype positive LQT patients have more than 1 mutation in >=1 gene. Biallelic pathogenic variants or digenic pathogenic variants appear to be generally associated with a more severe phenotype with longer QTc interval and a higher incidence of cardiac events. Note: loss of function variants in SCN5A are associated with Brugada syndrome and individual variants can have hybrid loss of function and gain of function effects causing a mixed phenotype.
Gene	MYBPC3
OMIM gene number	600958
Disease name	MYBPC3-related Hypertrophic Cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Inheritance	Autosomal dominant
Allelic requirement	Monoallelic autosomal
Inheritance qualifiers	Typified by incomplete penetrance
Disease-associated variant consequence	Decreased gene product level; altered gene product sequence
Variant classes reported with evidence of pathogenicity	Splice_region; splice_acceptor; splice_donor; frameshift; frameshift_variant_NMD_triggering; stop_gained; stop_gained_NMD_triggering; missense; inframe_insertion; inframe_deletion; intron_variant; structural_variants (whole exon deletions)
Potential novel variant classes based on predicted functional consequence	splice_acceptor_variant_NMD_escaping; splice_donor_variant_NMD_escaping; frameshift_variant_NMD_escaping; stop_gained_NMD_escaping; stop_lost; start_lost
Narrative summary MYBPC3 pathogenic variants cause HCM through decreased gene product level or altered gene product sequence either leading to a reduction in MyBP-C content in the sarcomere or altered function. The disease mechanism is loss of function; There is evidence of haploinsufficiency. Inheritance is usually autosomal dominant, typified by incomplete penetrance and variable expressivity. Homozygous and compound heterozygous variants have been reported and can lead to severe, early onset phenotypes. The majority of variants are heterozygous frameshift, nonsense, or splice site variants that result in premature termination codons. Missense and inframe indels are also frequently reported and a subset have been shown to cause loss of function through failure of myofilament incorporation and rapid degradation, further supporting haploinsufficiency as a mechanism. Variants in MYBPC3 affecting canonical splice site dinucleotides are a well-characterised cause of HCM. Recent work has identified more deeply intronic variants associated with disease.