The patient clinically diagnosed as DCM. A heterozygous missense variant, c.3373G>A, in exon 30 of the MYBPC3 (NM‐000256), was determined in the patient.
Case#: Female with DCM symptoms beginning at age 30
DiseaseAssertion: Dilated cardiomyopathy (DCM) associated with a heterozygous missense variant in MYBPC3, c.3373G>A (p.Val1125Met). The authors propose autosomal dominant inheritance in this DCM case.
FamilyInfo: NR – Detailed family relationships, segregation testing, and individual relatives' phenotypes are not described for the current DCM proband.
ParentalTesting: NR
CasePresentingHPOs: HP:0001644 (Dilated cardiomyopathy); HP:0002094 (Dyspnea); HP:0001962 (Palpitations); HP:0004756 (Ventricular tachycardia)
CaseHPOFreeText: The patient experienced symptoms beginning at age 30, including frequent palpitations and dyspnea. ECG monitoring revealed multiple premature ventricular contractions and nonsustained ventricular tachycardia. Echocardiography demonstrated severe spherical left ventricular enlargement, severe systolic and diastolic dysfunction, LVEF of 10%, and mild pulmonary hypertension. She was classified as NYHA functional class II–III and received medical therapy and an implantable cardioverter-defibrillator.
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
CasePreviousTesting: NR – Article describes patient's clinical evaluation, including ECG monitoring and echocardiography, before genetic analysis.
Genotyping Method: Genomic DNA was extracted from peripheral blood. Targeted next-generation sequencing was performed using a custom NimbleGen panel covering the coding regions and exon–intron boundaries of 23 genes associated with DCM. Sequencing was conducted on an Illumina HiSeq 2000 platform. Reads were aligned to the hg19 reference genome using BWA, and SAMtools was used for variant analysis. MYBPC3 variant confirmed using Sanger sequencing.
FunctionalAnalysis: In silico analyses were performed to investigate the potential functional consequences of MYBPC3 p.Val1125Met. SIFT, PolyPhen-2, and MutationTaster predicted potentially damaging effects, while CADD produced a score of 33. Multiple-sequence alignment demonstrated that Val1125 is highly conserved across species. Protein modeling using I-TASSER and Phyre2 predicted structural differences involving the region surrounding residue 1125, located within the C9 fibronectin type III domain of cardiac myosin-binding protein C (cMyBP-C). The authors proposed that the substitution could affect protein structure and function. No direct experimental functional validation of this variant was reported.
Variant: MYBPC3 NM_000256.3:c. 3373G>A (p.Val1125Met); rsID: rs121909378; missense; heterozygous
ClinVar: 8604
CAID: CA014038
gnomAD: MYBPC3 c.3373G>A (p.Val1125Met), GRCh38: 11-47332931-C-T. In gnomAD v4, the reported allele frequencies are 0.00001920 (exomes), 0.00003943 (genomes), and 0.00002111 (total). The highest ancestry-specific allele frequency identified was in the Ashkenazi Jewish population (AC = 5; AF = 0.0001695).
AdditionalInfo: Authors propose variant dosage, interactions with other variants, and genetic modifiers may contribute to differences in disease phenotype. However, the proposed autosomal dominant association with DCM was not supported by documented segregation testing in the current proband's family, and the functional analyses were computational rather than experimental.