Case# NonNew, male, 40yr

CasePresentingHPOs HP:0002119, HP:0002375 , HP:0031317

CaseNotHPOs Annotate with the HPOs that were noted not to manifest within the proband of interest.

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseMethod2 as mentioned

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.1073C>T (p.Ser358Leu)

ClinVar 734

VariantEvidence ?????Surely the presenting relevant phenotypes is not enough, neither are the in silico programs they are running forpathogenicity prediction. There seems to be nothing else provided????

CaseAddInfo De Novo, Maternity/Paternity confirmed

Case# Baskin RW, Female, 31

CasePresentingHPOs HP:0004756, HP:0011841, HP:0002013

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.934C>T (p.Arg312Trp)

ClinVar 36873

gnomAD 0.03553 link

Case# Baskin TS, Male, 16

CasePresentingHPOs HP:0006956, HP:0100749, HP:0001962, HP:0004756

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.829A>T (p.Thr277Ser)

ClinVar 165456

gnomAD 0.006432 link

Case# Baskin EK, Female, 47

CasePresentingHPOs HP:0010872, HP:0100660

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.424G>A (p.Glu142Lys)

ClinVar 46147

gnomAD 0.001121 link

Case# Baskin YH, Male, 12

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.1111T>C (p.Tyr371His)

ClinVar 46140

gnomAD 0.01076 link

Case# Baskin AT, Male

CasePresentingHPOs HP:0004756, HP:0002119, HP:0010872

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.169G>A (p.Ala57Thr)

ClinVar 88981

gnomAD 0.001381 link

Case# B1-3, Male, UK

CasePresentingHPOs HP:0001279

CasePreviousTesting re-sequenicing of genome

CaseGenotypingMethod genotyped for five microsatellite markers spanning TMEM43 on chromosome 3p25

Variant NM_024334.2(TMEM43):c.934C>T (p.Arg312Trp)

ClinVar 36873

gnomAD 0.03553 link

Case# A4, Male, UK

CasePreviousTesting re-sequenicing of genome

CaseGenotypingMethod genotyped for five microsatellite markers spanning TMEM43 on chromosome 3p25

Variant NM_024334.2(TMEM43):c.424G>A (p.Glu142Lys)

ClinVar 46147

gnomAD 0.001121 link

Case# B12, Male, UK

CasePresentingHPOs HP:0010872

CasePreviousTesting re-sequenicing of genome

CaseGenotypingMethod genotyped for five microsatellite markers spanning TMEM43 on chromosome 3p25

Variant NM_024334.2(TMEM43):c.934C>T (p.Arg312Trp)

ClinVar 36873

gnomAD 0.03553 link

Case# B1-4, Male, UK

CasePresentingHPOs HP:0001279

CasePreviousTesting re-sequenicing of genome

CaseGenotypingMethod genotyped for five microsatellite markers spanning TMEM43 on chromosome 3p25

Variant NM_024334.2(TMEM43):c.934C>T (p.Arg312Trp)

ClinVar 36873

gnomAD 0.03553 link

Case# A2, Male, UK

CasePresentingHPOs HP:0002119

CasePreviousTesting re-sequenicing of genome

CaseGenotypingMethod genotyped for five microsatellite markers spanning TMEM43 on chromosome 3p25

Variant NM_024334.2(TMEM43):c.934C>T (p.Arg312Trp)

ClinVar 36873

gnomAD 0.03553 link

Case# B4, Male, UK

CasePreviousTesting re-sequenicing of genome

CaseGenotypingMethod genotyped for five microsatellite markers spanning TMEM43 on chromosome 3p25

Variant NM_024334.2(TMEM43):c.424G>A (p.Glu142Lys)

ClinVar 46147

gnomAD 0.001121 link

Case# HondaF, female, newborn

CasePresentingHPOs HP:0001640, HP:0006682, HP:0011713, HP:0100572

CaseGenotypingMethod "gene analysis"

Variant NC_000003.10:g.14147425G>A

CAID CA052413

gnomAD 0.001044 link

CaseAddInfo 2 mutations in cis from mom, phenotypes described at birth (usually adult onset)

MiltingF1

FamilyNotHPOs HP:0100660, HP:0004756, HP:0001645, HP:0031317

CountryOrigin Germany

Ethnicity Danish

Family#PreviousTesting: whole genome Family#Method1 PCR

Family#GenotypingMethod Liquid Chromatography screening

Affected 8

Unaffected 6

Segregations 7

eLOD 2.1

ProbandLabel Milting3:1 female

Variant NM_024334.2(TMEM43):c.1073C>T (p.Ser358Leu)

ClinVar 734

Family#PresentingHPOs HP:0031317, HP:0011663

FamilyNotHPOs HP:0001635

CountryOrigin Newfoundland

Ethnicity NonHispanic/Latino

Race White

Family#PreviousTesting No

Family#GenotypingMethod Bidirectional resequencing

ClinVar NM_024334.2(TMEM43):c.1073C>T (p.Ser358Leu), ClinVarID: 734

FamilyPMIDs 3386698

NonPatientCell HL-1 atrial cell line, BTO:0003264

GeneFunction nuclear membrane organization, GO:0071763

GeneAlteration constructs consisting of full length wild-type and mutant (p.S358L) human TMEM43 tagged at the C-terminus with GFP were used to generate stably transfected HL-1 cells.

CellPhenotype HP:0011675 Arrhythmia

CellEvidence 1.2 cm/s slower electrical conduction velocity than WT and control (40% reduction)

FAVariants NM_024334.2(TMEM43):c.1073C>T, CA ID: 734

Same well known TMEM is tested: NM_024334.2(TMEM43):c.1073C>T (p.Ser358Leu) ClinVarID: 734

Case# Christensen B

CasePresentingHPOs HP:0011675 Arrhythmia, HP:0010872 T-Wave Inversion, HP:0005133 Right Ventricular Dilation, HP:0031317 Fatty replacement of ventricular myocardial tissue

CasePreviousTesting amplicons were pre‐screened on a LightScanner High‐Resolution Melting Curve Analysis System

CaseMethod1 PCR

CaseGenotypingMethod (PCR) amplification was performed for all TMEM43 exons and flanking introns.

Variant NM_024334.2(TMEM43):c.1073C>T (p.Ser358Leu)

ClinVar 734

VariantEvidence Is there any??????

Case# Christensen A, 59 diagnosis, male

CasePresentingHPOs HP:0004756 Ventricular Tachycardia, HP:0010872 T-Wave Inversion, HP:0005133 Right Ventricular Dilation, HP:0031317 Fatty replacement of ventricular myocardial tissue

CasePreviousTesting amplicons were pre‐screened on a LightScanner High‐Resolution Melting Curve Analysis System

CaseMethod1 PCR

CaseGenotypingMethod (PCR) amplification was performed for all TMEM43 exons and flanking introns.

Variant NM_024334.2(TMEM43):c.705+7G>A

ClinVar 46152

gnomAD 0.0007554 link

VariantEvidence N/A