FamilyLabel: Van Driest Family

Family#PresentingHPOs: HP:0001639 (hypertrophic cardiomyopathy)

FamilyNotHPOs:

CountryOrigin:

Ethnicity:

Race:

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)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: None for the proband

CaseMethod1:

CaseMethod2:

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:

FamilyLabel: Van Driest Family

Family#PresentingHPOs: HP:0001639 (hypertrophic cardiomyopathy)

FamilyNotHPOs:

CountryOrigin:

Ethnicity:

Race:

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)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: None for the proband

CaseMethod1:

CaseMethod2:

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

PMID: PMID:16043485

Gene: TPM1

Disease: hypertrophic cardiomyopathy 3

MonDO: MONDO:0007267

InheritancePattern: AD