Case#: Patient A

DiseaseAssertion: Dilated Cardiomyopathy (DCM)

FamilyInfo: Large multigenerational family with DCM. Six family members identified. TPM1 and VCL variants are connected to disease.

ParentalTesting: Both parents presented with DCM and TPM1 variant c.97G>A.[p.glu33Lys, p.E33K].

CasePresentingHPOs: HP:0001644 HP:0012664 HP:0001635

CaseHPOFreeText: severe heart failure and required heart transplant. Left ventricular ejection fraction.

CaseNotHPOs:unkown

CaseNotHPOFreeText: unkown

CasePreviousTesting: unkown

Genotyping Method: PCR amplification & Sanger sequencing.

FunctionalAnalysis: functional data support that TPM1 and VCL variants act synergistically to impact cardiomyocyte contractility and sarcomeric organization and suggest that together these variants may perturb sarcomeric–costameric interactions.

Variant: TPM1 c.97G>A (p.Glu33Lys; E33K)

ClinVar: not found

CAID: CA018447

gnomAD: not reported

AdditionalInfo:

PMID: PMID:27057166

Gene: TPM1

Disease: hypertrophic cardiomyopathy 3

MonDO: MONDO:0007267

InheritancePattern: AD

ExperimentName: Ojala 2016 hiPSC-derived CMs

PatientCell: CL_0002620 (skin fibroblasts)

GeneFunction: GO:0008016 (regulation of heart contraction)

GeneAlteration: hiPSC-derived cardiomyocytes (CMs) generated from skin fibroblasts collected from patients carrying a TPM1-Asp175Asn mutation

FunctionalEvidence: Figure 2 shows enlarged cardiomyocytes (CMs) (a-b), an increase in multinucleated CMs (c), and calcium handling abnormalities (d) for the HCM-TPM1 variant CMs compared to WT CMs.

FAVariants: NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn), CA018106

ExperimentName: Karibe 2001 In vitro motility

NonPatientCell: mechanical actin-myosin functional assay

GeneFunction: GO:0030049 (muscle filament sliding)

GeneAlteration: PCR-based mutagenesis of Ala to Ser was used at nucleotide position 340 (GenBank M19713) to produce cDNA encoding the V95A variant. This coding sequence was inserted into the pET3d expression vector and the wild-type or mutant tropomoysin protein was expressed in DE3 cells before being purified to homogeneity for use in the in vitro assays.

FunctionalEvidence: Mutant tropomyosin-containing actin-troponin-tropomyosin filaments combined with rhodamine-phalloidin had slightly decreased (5%) sliding speed on a heavy meromyosin-coated surface compared to wild-type tropomyosin-containing filaments under saturating calcium conditions (Table 1).

FAVariants: NM_001018005.2(TPM1):c.284T>C (p.Val95Ala), CA017934

Case#: Family MI, Northern European

CasePresentingHPOs: HP:0001639

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CaseGenotypingMethod: PCR amplification followed by Cycle Sequencing

Variant: The nucleotide variant positions here refer to those described in the initial cloning of the gene in 1988 (PMID: 3336363), but nucleotide G579A here aligns to NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn).

ClinVar: 12456

CAID: CA018106

gnomAD: Grpmax FAF = 7.900e-7, SNV: 15-63060899-G-A, gnomADv4_D175N

VariantEvidence:

CaseAddInfo:

CasePMIDs: PMID:8327508

Case#: Family MZ, Northern European

CasePresentingHPOs: HP:0001639 ( Hypertrophic cardiomyopathy)

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CaseGenotypingMethod: PCR amplification followed by Cycle Sequencing

Variant: The nucleotide variant positions here refer to those described in the initial cloning of the gene in 1988 (PMID: 3336363), but nucleotide A595G here aligns to NM_001018005.2(TPM1):c.539A>G (p.Glu180Gly).

ClinVar: 12455

CAID: CA019017

gnomAD: 15-63060915-A-G not in gnomAD v4.0.0

VariantEvidence:

CaseAddInfo:

CasePMIDs: PMID:8327508

Case#: Proband_DBIII-2, 53 y.o., M

CasePresentingHPOs: HP:0001712

CaseHPOFreeText: Max LVWT 18 mm; LA size 40 mm; episode of sustained VT

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CasePreviousTesting: None

CaseMethod1: PCR amplification of TPM1 exon 5 followed by cycle sequencing

CaseMethod2: STR polymorphisms to construct haplotypes

CaseGenotypingMethod: PCR amplification of TPM1 exon 5 followed by cycle sequencing

Variant: The nucleotide position 579 refers to that described in the initial cloning of the gene in 1988 (PMID: 3336363), but aligns to NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn).

ClinVar: ClinVar:12456

CAID: CA018106

gnomAD: Grpmax FAF = 7.900e-7, SNV: 15-63060899-G-A, gnomADv4_D175N

CasePMIDs:

FamilyLabel: Van Driest Family

Family#PresentingHPOs: HP:0001639 (hypertrophic cardiomyopathy)

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Family#PreviousTesting: Three highly polymorphic markers for each of 9 known HC genes (MYH7, TNNT2, TNNI, TPM1, MYL3, MYL2, MBPC, ACTC, and PRKAG2) were PCR-amplified for haplotype analysis. Only 3 candidate genes, MYL3, TNNT2, and TPM1, were shared by proband, affected siblings, and father.

Family#Method1: (other) PCR amplification of all protein-coding exons and splice junctions of the 3 candidate genes from genomic DNA was analyzed using DHPLC (denaturing high-performance liquid chromatography).

Family#Method2: Cycle sequencing was performed on all DHPLC amplicons with abnormal elution profiles (exon 5 of TPM1).

Family#GenotypingMethod: DHPLC screening followed by cycle sequencing of TPM1 exon 5.

Affected: 4

Unaffected:

Segregations: 3 (Figure 1)

PublishedLOD: N/A

eLOD: N/A; < 4 segregations

AddSegregationInfo:

ProbandLabel: III-1

Variant: NM_001018005.2(TPM1):c.554T>G (p.Leu185Arg)

ClinVar: 31881

CAID: CA019057

gnomAD: 15-63060930-T-G has no data in gnomAD v4.0.0

FamilyAddInfo: TPM1 variant reported as c.T610G (p.L185R), using coding positions relative to GeneBank accession M19713.1?

FamilyPMIDs:

Case#: III-1

CasePresentingHPOs: HP:0001639 (hypertrophic cardiomyopathy); HP:0001645 (sudden cardiac death)

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CasePreviousTesting: None for the proband

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CaseGenotypingMethod: DNA extracted from paraffin-embedded spleen tissue, taken at autopsy, was subjected to PCR-amplification of TPM1 exon 5 followed by cycle sequencing to confirm presence of the familial TPM1 variant.

Variant: NM_001018005.2(TPM1):c.554T>G (p.Leu185Arg)

ClinVar: 31881

CAID: CA019057

gnomAD: 15-63060930-T-G has no data in gnomAD v4.0.0

VariantEvidence: Chang, et al. 2005 (PMID:16043485) demonstrated in ATPase activity assays that myofibrils reconstituted with L185R mutant tropomyosin had an increased sensitivity to calcium compared to wild-type tropomyosin-reconstituted myofibrils.

CaseAddInfo: No other genes were screened for mutations in this proband.

CasePMIDs:

PMID: PMID:16043485

Gene: TPM1

Disease: hypertrophic cardiomyopathy 3

MonDO: MONDO:0007267

InheritancePattern: AD