Case#: An El-Salvadoran 22-year-old female

DiseaseAssertion: Restrictive cardiomyopathy (RCM), associated with sarcomeric gene variants in MYL3 and MYL2

FamilyInfo: The patient’s mother was the only family member available for evaluation (Fig 2). On genetic testing she was found to be a double heterozygote for the p.Glu143Lys mutation in MYL3 and the p.Gly57Glu mutation in MYL2. She had a normal transthoracic echocardiogram, electrocardiogram, and physical exam at 45 years of age

ParentalTesting: Patients mother

CasePresentingHPOs: HP:0002099, HP:0012378, HP:0012764, HP:0001962, HP:0034807, HP:0001541, HP:0001410, HP:0031667, HP:0004749,

CaseHPOFreeText: diagnosed with RCM and advanced heart failure requiring heart transplantation. A prior diagnosis of childhood asthma presented with worsening fatigue and dyspnea on exertion over the course of 12 months. She reported having frequent episodes of shortness of breath as a child, also reported orthopnea, paroxysmal nocturnal dyspnea, and palpitations; her heart failure symptoms were classified as NYHA Class III–IV. did have ascites suggestive of congestive hepatopathy. Her cardiovascular examination revealed a nondisplaced, nonsustained point of maximal impulse, with a mild parasternal lift without a pulmonary artery tap.She had a normal S1, but P2>A2. She had an S3, but no S4. She had a soft I/IV holosystolic murmur over the apex; no knock or rub. Her electrocardiogram demonstrated atrial flutter with an atrial rate of 250–300 and a ventricular rate of 85.

CaseNotHPOs: HP:0002321, HP:0001279, HP:0010741

CaseNotHPOFreeText: She denied dizziness, syncope, and lower extremity edema.

CasePreviousTesting: The patient's mother was also tested to assess inheritance.

Genotyping Method: Sarcomere gene sequencing

FunctionalAnalysis: MYL2 p.Gly57Glu variant using sequence conservation and computational splice-site prediction

Variant: NM_000432.4:c.170G>A

ClinVar:43458

CAID: CA009910

gnomAD: gnomAD v2 12:111352094 C / T https://gnomad.broadinstitute.org/variant/12-111352094-C-T?dataset=gnomad_r2_1 gnomAD v3 12:110914290 C / T https://gnomad.broadinstitute.org/variant/12-110914290-C-T?dataset=gnomad_r3 , gnomAD v4 chr12-110914290-C-T https://gnomad.broadinstitute.org/variant/chr12-110914290-C-T?dataset=gnomad_r4