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    Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy
    2
    1. ClingenBaseline 24 Oct 2026
      Myasthenia gravis, T2DM, HepC, PVC, PACs, PSVT, SND59MYOZ2: c.488T>C p.(Leu163Ser)#905 (M)30NAYesYes/noH-txNAMYH7: c.2302G>C p.(Gly768Arg) MYOM1: c.1655G>A p.(Gly552Asp)#906 (F)5815NoNo/noNoneNAMYBPC3: c.3617G>A p.(Gly1206Asp)#907 (M)37<15aNoNo/noECG abnormalities60MYOM1: c.432-1G>T#908 (M)20<15bNoYes/noH-tx, T2DM50MYH6: c.5111C>T p.(Ala1704Val)#909 (M)31<15aNoYes/noNone75MYBPC3: c.1409G>A p.(Arg470Gln)#910 (F)1723NoNo/noNone76MYBPC3: c.639C>A p.(Tyr213*)#913 (M)1219NoNo/noAngiokeratomas right ear hearing loss Visual impairment hypothyroidism, AF, NSVT60MYBPC3: c.649A>G p.(Ser217Gly) GLA: c.718_719delAA p.(Lys240Glufs*9) MYH6: c.3883G>C p.(Glu1295Gln)914 (M)2234YesNo/noHOCM, LGE at CMR imaging, NSVT65MYBPC3: c.506-2A>C { label (or @symbol) needed for fn[@id='tfn12-ijmm-38-04-1111'] } Bold font indicates mutations in MYH6 and in genes encoding non-TTm proteins that would not been identified without NGS analysis. a Diagnosis of borderline HCM; b original diagnosis of borderline HCM has been modified in dilated cardiomyopathy. PAC, premature atrial contractions; H-tx, heart transplantation; T2DM, type 2 diabetes mellitus; LVWT, left ventricular wall thickness; SND, sinus node dysfunction; AF, atrial fibrillation; hep C, hepatitis C; LBBB, left bundle branch block; AICD, automatic implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; SCD, sudden cardiac death; LGE, late gadolinium enhancement; CMR, cardiac magnetic risonance; NSVT, non-sustained ventricular tachycardia; PVC, premature ventricular contractions; HOCM, hypertrophic obstructive cardiomyopathy; PSVT, paroxysmal supraventricular tachycardia; NA, not available; NGS, next generation sequencing; HCM, hypertrophic cardiomyopathy.

      Case: Cecconi_Patient#903, female, 52 yrs old at onset of HCM

      CasePresentingHPOs:

      CasePresentingHPOsFreeText: In adults, a maximal LV wall thickness (LVWT) ≥15 mm; the maximal LVWT between 10 and 14 mm, in conjunction with other features (i.e., family history, electrocardiogram abnormalities) prompted the diagnosis of borderline HCM.

      CaseNOTHPOs:

      CaseNOTHPOSFreeText:

      CasePreviousTesting: The clinical diagnosis of primary HCM was based on medical history, a physical examination and on the echocardiographic demonstration of a hypertrophied left ventricle (LV) that could not be explained by another cardiac or systemic disease.

      CaseGenotypingMethod: NGS, Sanger Targeted NGS panel to simultaneously analyze a total of 19 genes encoding not only TTm proteins, but also other sarcomeric proteins and some non-sarcomeric proteins that cause HCM phenocopies. Sanger sequencing to ensure a depth of coverage >20X for each target nucleotide.

      Variant: c.488T>C p.(Leu163Ser)

      ClinVarID: or CAID: 45784, CA282614

      gnomAD: MAF=0.001724 in African/African Americans (43/24948 alleles), total allele frequency=0.0001521. No homozygotes. v2.1.1

      AddCaseInfo: Pt has LVWT of 18, LVEF of 59%, and other medical issues (myasthenia gravis, T2DM, HepC, PVC, PACs, PSVT, and SND

      PreviouslyPublished: no

      VariantEvidence: none

      CaseInfo Individual MYOZ2 inferred_gene_hgnc:1330 inferred_gene_source:CAID UNC Biocuration Core
    2. ClingenBaseline 23 Oct 2026
      No. of patient (gender)Age at onset (years)LVWT (mm)AICD (yes, no)Family history of HCM/SCD (yes, no/yes, no)Other medical (recurrent or episodic) issuesLVEF (%)Mutations#94 (F)3024NoNo/noNone65MYBPC3: c.1174delG p.(Ala392fsX405) MYH7: c.161G>T p.(Arg54Leu)a TNNT2: c.832C>T p.(Arg278Cys) MYOM1: c.2087G>A p.(Arg696His)#241 (F)17<15bNoNo/noH-tx44TNNT2: c.83C>T p.(Ala28Val) LAMP2: c.741+1G>T MYOM1: c.1514A>C p.(Glu505Ala)#314 (M)4821NoYes/noHistory of hypertension62MYBPC3: c.1458-1G>A MYOM1: c.139A>G p.(Ser47Gly) MYOM1: c.2110G>A p.(Glu704Lys) MYH6: c.3883G>C p.(Glu1295Gln)#656 (M)5615NoNo/noAF, NSVT65MYBPC3: c.2610del p.(Ser871AlafsX8) GLA: c.937G>T p.(Asp313Tyr)#692 (F)6522NoYes/noHistory of hypertension65MYBPC3: c.1624G>C p.(Glu542Gln) MYOZ2: c.36A>C p.(Lys12Asn)#748 (F)1617YesYes/yesNSVT, AF, WPW syndrome60MYH7: c.5287G>A p.(Ala1763Thr) LAMP2: c.928G>A p.(Val310Ile)#787 (M)4532YesYes/noDyslipidemia, nodular thyroid disease, NSVT, AF, AFL60MYBPC3: c.2429G>A p.(Arg810His) MYBPC3: c.3370T>C p.(Cys1124Arg) CAV3: c.216C>G p.(Cys72Trp)#800 (F)2516NoYes/yesNone50TNNT2: c.536C>T p.(Ser179Phe) MYH6: c.5797-2A>G MYH6: c.5476_5477delinsAA p.(Gly1826Asn)#834 (F)1424YesYes/yesLGE at CMR imaging68TNNT2: c.275G>A p.(Arg92Gln) CAV3: c.233C>T p.(Thr78Met)#854 (M)4619NoYes/noNone60MYBPC3: c.506-2A>C ANKRD1: c.827C>T p.(Ala276Val)#865 (M)1428YesYes/noHOCM, myocardial bridge on AIA, v-fib60MYL2: c.401A>C p.(Glu134Ala) MYL2: c.206T>C p.(Met69Thr) { label (or @symbol) needed for fn[@id='tfn6-ijmm-38-04-1111'] } Bold font indicates additional mutations in MYH6, MYL2 or in genes encoding non-TTm proteins identified only by NGS analysis. a Uncovered regions: mutation identified only by Sanger sequencing; b Original borderline diagnosis of HCM has been modified in dilated cardiomyopathy. WPW, Wolff-Parkinson-White; AICD, automatic implantable cardioverter defibrillator; H-tx, heart transplantation; LVWT, left ventricular wall thickness; AF, atrial fibrillation; NSVT, non-sustained ventricular tachycardia; AFL, atrial flutter; LGE, late gadolinium enhancement; AIA, anterior interventricular artery; CMR, cardiac magnetic risonance; v-fib, ventricular fibrillation; HOCM, hypertrophic obstructive cardiomyopathy; LVEF, left ventricular ejection fraction; SCD, sudden cardiac death; NGS, next generation sequencing; HCM, hypertrophic cardiomyopathy.

      Case: Cecconi_Patient#692, female, 65 yrs old at onset of HCM

      CasePresentingHPOs:

      CasePresentingHPOsFreeText: In adults, a maximal LV wall thickness (LVWT) ≥15 mm; the maximal LVWT between 10 and 14 mm, in conjunction with other features (i.e., family history, electrocardiogram abnormalities) prompted the diagnosis of borderline HCM.

      CaseNOTHPOs:

      CaseNOTHPOSFreeText:

      CasePreviousTesting: The clinical diagnosis of primary HCM was based on medical history, a physical examination and on the echocardiographic demonstration of a hypertrophied left ventricle (LV) that could not be explained by another cardiac or systemic disease.

      CaseGenotypingMethod: NGS, Sanger Targeted NGS panel to simultaneously analyze a total of 19 genes encoding not only TTm proteins, but also other sarcomeric proteins and some non-sarcomeric proteins that cause HCM phenocopies. Sanger sequencing to ensure a depth of coverage >20X for each target nucleotide.

      Variant: c.36A>C, p.(Lys12Asn)

      ClinVarID: or CAID: 1493383, CA104969015

      gnomAD: MAF=0.0001635 in (1/6118 alleles), total allele frequency=0.000003986. No homozygotes. v2.1.1

      AddCaseInfo: Pt has LVWT of 22, family history of HCM, LVEF% of 65, and history of hypertension. Pt also has a variant in MYBPC3 (c.1624G>C p.Glu542Gln)

      PreviouslyPublished: no

      VariantEvidence: none

      Individual CaseInfo MYOZ2 inferred_gene_hgnc:1330 inferred_gene_source:CAID UNC Biocuration Core
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