Case#: Family #6; 36-year-old male

DiseaseAssertion: Arrhythmogenic right ventricular cardiomyopathy (ARVC); diagnosed according to the 2010 revised Task Force Criteria

FamilyInfo: Family #6. No informative segregation evidence specifically linking the MYL3 variant to ARVC was reported. The authors noted that family screening was incomplete or normal in other families, but did not specify which circumstance applied to Family #6.

ParentalTesting: NR

CasePresentingHPOs: HP:0006682 (PVCs)

CaseHPOFreeText: Symptomatic presentation; major right ventricular structural abnormality; minor ECG repolarization criterion; 1,181 ventricular ectopic beats on Holter monitoring; sustained ventricular arrhythmia (specific rhythm not reported).

CaseNotHPOs: HP:0001279 (Syncope); HP:0005162 (Abnormal left ventricular function)

CaseNotHPOFreeText: No cardiac syncope or left ventricular dysfunction reported. Absence of cardiac syncope does not necessarily exclude every form of syncope.

CasePreviousTesting: No pathogenic or likely pathogenic variants identified in established ARVC-associated genes (PKP2, DSG2, DSP, DSC2, JUP, TMEM43, PLN, SCN5A). Subsequent screening included nine sarcomere genes: ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1. The study used broad genetic testing, including whole-exome sequencing in a subset of probands; whether Family #6 underwent whole-exome sequencing was not specified.

Genotyping Method: Sarcomere-gene sequencing and deletion/duplication analysis through clinical cardiomyopathy panels, research-based next-generation sequencing panels, or whole-exome sequencing. The exact initial platform for Family #6 was not specified. Identified variants were confirmed by PCR amplification and Sanger sequencing.

FunctionalAnalysis: NR

Variant: MYL3 NM_000258.2:c.461G>A (p.Arg154His); missense variant; exon 4

ClinVar: 14062

CAID: CA013861

gnomAD: MYL3 c.461G>A (p.Arg154His), GRCh38: 3-46859495-C-T. gnomAD v4: Exome AF = 0.00003557; Genome AF = 0.00001971; Total AF = 0.00003408. European (non-Finnish): AC = 52, AF = 0.00004407. https://gnomad.broadinstitute.org/variant/3-46859495-C-T?dataset=gnomad_r4

AdditionalInfo: Murray et al. (2018), Tables 1 and 2, Family #6. The MYL3 variant was classified as likely pathogenic (LP) according to ACMG criteria, with a PolyPhen-2 score of 0.861. The proband met criteria for definite ARVC, with no reported left ventricular dysfunction. Although the variant was rare and computationally predicted to be damaging, the authors emphasized that evidence demonstrating a causal relationship between sarcomere variants and ARVC remained insufficient. No direct functional analysis of this variant was performed in the study.