Case#: 31 year old man of European ancestry. Patient ID NR.

DiseaseAssertion: Nonischemic dilated cardiomyopathy.

FamilyInfo: No reported family history of dilated cardiomyopathy. Both parents had normal heart exams and echocardiograms.

ParentalTesting: Both biological parents tested negative for the TPM1 variant. Sequencing coverage was 500 to 600×. The authors thought the variant likely arose de novo. They could not rule out parental germline mosaicism.

CasePresentingHPOs: HP:0001644, HP:0025169, HP:0001635, HP:0001640, HP:0002202, HP:0002875, HP:0002094, HP:0012764, HP:0034807

CaseHPOFreeText: He first felt short of breath during activity. Later he felt short of breath at rest. He also had a persistent cough and abdominal swelling. Chest CT showed an enlarged heart and fluid around both lungs. The echo showed that both ventricles were enlarged and pumped poorly. His left ventricular ejection fraction was 12%. His heart failure worsened and he needed a heart transplant.

CaseNotHPOs: HP:4000004 (no myocardial late gadolinium enhancement on cardiac MRI).

CaseNotHPOFreeText: The biopsy and exam of the removed heart did not show evidence of active myocarditis.

CasePreviousTesting: NR

Genotyping Method: The Invitae Dilated Cardiomyopathy Panel used next generation sequencing to test 41 genes.

FunctionalAnalysis: Thin filaments with T237S needed more calcium to reach the same level of activation. At low calcium the mutant filaments were less likely to be open and myosin ATPase activity was lower. Omecamtiv mecarbil restored calcium sensitivity in the lab assay. See Figures 3 through 5 and Tables 1 and 2.

Variant: NM_001018005.2(TPM1):c.710C>G (p.Thr237Ser). Heterozygous.

ClinVar: 1067773

CAID: CA392724554

gnomAD: No variant record found in gnomAD v4.1.

AdditionalInfo: PMID 36739943. Figure 1 shows the echo and biopsy results. The clinical report called the variant a VUS. The study authors considered it likely pathogenic after lab testing.