Case#: 17-year-old African American male

DiseaseAssertion: Symptomatic paroxysmal atrial fibrillation (AF)

FamilyInfo: Proband's mother experienced symptomatic early-onset paroxysmal AF at 47 years of age. Proband's maternal grandmother presented with minimally symptomatic AF at 52 years of age.

ParentalTesting: Proband, mother, and maternal grandmother tested positive for SCN5A variant.

CasePresentingHPOs: HP:0005110, HP:0004757

CaseHPOFreeText: Symptomatic paroxysmal atrial fibrillation. The initial presenting ECG revealed AF with controlled ventricular rates in the absence of atrioventricular (AV) nodal blockers.

CaseNotHPOs: HP:0001678

CaseNotHPOFreeText: absence of atrioventricular (AV) nodal blockers, LA and LV size normal.

CasePreviousTesting: NR

FunctionalAnalysis: The biophysical properties of the SCN5A-N470K mutant channel were investigated using voltage-clamp recordings following the transient transfection of HEK cells with either wild-type (WT) or N470K channels. The impact of the N470K mutation on the gating properties of the Nav1.5 sodium channel was also investigated. Findings indicate that a gain-of-function mutation.

Variant: 1410C>G (p.Asp470Lys)

ClinVar: 30047

CAID: CA014836

gnomAD: https://gnomad.broadinstitute.org/variant/3-38646328-G-C?dataset=gnomad_r2_1 (FAF: 0.0001656, African/African American)

AdditionalInfo: Clinical characteristics of proband and family members found in Table 1.

PMID: 41567847

Gene: SCN5A

HGNC ID: 10593

Case#: 7-year-old boy

DiseaseAssertion: Atrial flutter (AFL), sick sinus syndrome (SSS), Brugada syndrome (BrS)

FamilyInfo: Family history of sudden death in maternal grandfather at age 30 years. Family testing identified the same SCN5A variant in the proband's mother and sister. The mother was asymptomatic but had a coved type ST elevation in V1 lead recorded at the 3rd intercostal position (Fig. 1e) and remained free of cardiac events until age 37 years. His sister's ECG was normal, and she remained free of cardiac events for 10 months

ParentalTesting: Mother was found to have the same LOF variant

CasePresentingHPOs: HP:0004749, HP:0011712, HP:0011704, HP:0011654

CaseHPOFreeText: AFL detected on ECG with right bundle branch block but no history of arrhythmia, congenital heart disease, or cardiomyopathy. Post-RFCA, patient had sinus arrest lasting up to 7s, leading to diagnosis of sick sinus syndrome (SSS). Post-ablation ECG following a second RFCA revealed Brugada-type patterns, raising suspicion of Brugada syndrome (BrS) which eventually lead to a diagnosis.

CaseNotHPOs: HP:0001638, HP:0001279, HP:0011675

CaseNotHPOFreeText: Cardiomyopathy, syncope, arrhythmia

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: NR

Variant: c.2678G > A p.Arg893His

ClinVar: 67749

CAID: CA016396

gnomAD: https://gnomad.broadinstitute.org/variant/3-38585800-C-T?dataset=gnomad_r4 (v4.1.0 GrpMax FAF: 0.000003390 (European non-Finnish) )

PMID: 40697204

Gene: SCN5A

HGNC ID: 10593