Case5: 65 year-old male

DiseaseAssertion: carried a known TNNT2 K247R mutation as well as two novel intronic variants in MYH7 (IVS39+7C>A) and MYBPC3 (IVS25+13T>A)

FamilyInfo: None of his five siblings were affected, judged by their clinical presentation, nor was there any history of cardiac disease or sudden death in the family.

ParentalTesting:NR

CasePresentingHPOs:HP:0003677, HP:0012828, HP:0001635, HP:0005110, HP:0034307, HP:0012666,

CaseHPOFreeText: had late-onset at age 47 IDC, with a slow progression to severe heart failure and subsequently HTX. He also suffered from atrial fibrillation in the later stages of his disease. Had left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)) with a value of 68mm and 3.4cm/m2. As well with 30% of left ventricular ejection fraction. His ECG is normal, clinical status is heart transplantation from the age of 56. CAG is normal.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method:Genetically screened, also using GenBank with PCR by amplifying the coding region

FunctionalAnalysis: The variant could thus possibly result in the synthesis of a limited amount of the slightly modified β-myosin. The functional significance of this is not easily established, but it suggests that the variant may be a disease modifier.

Variant:NM_001276345.2:c.869A>G

ClinVar:4881578

CAID:CA344201883

gnomAD:NR

AdditionalInfo: MYH7 (IVS39+7C>A) increased the likelihood of a cryptic donor splice site to 70%, possibly resulting in the synthesis of mRNA coding for a β-myosin with a C terminus of –VGLE instead of –GLNEE. As the variant is located in the last exon, the faulty spliced mRNA is probably not degraded but results in the synthesis of a modified protein.