Supplementary Data: Table S3

Case 56:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CaseHPOFreeText: >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio > 2.3:1

CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.

CaseGenotypingMethod: WES, variant enrichment analysis

Variant: NM_000257.3(MYH7):c.4717G>A (p.Glu1573Lys)

ClinVar: 222729, https://www.ncbi.nlm.nih.gov/clinvar/variation/222729/

gnomAD: 0.00005967, https://gnomad.broadinstitute.org/variant/14-23885449-C-T

MultipleGeneVariants:

(1) TMPO Variant:

Variant: NM_003276.2(TMPO):c.821G>A (p.Arg274Lys)

ClinVar: 44673, https://www.ncbi.nlm.nih.gov/clinvar/variation/44673/

gnomAD: 0.002714, https://gnomad.broadinstitute.org/variant/12-98926856-G-A

PMID: 42074559

Gene: MYL2

HGNC ID: 7583

CaseP4-GAA: female, ethnicity = European, country origin = Italy

CasePresentingHPOs:

HPOsFreeText: enzyme activity = 2.22

CaseNotHPOs: HP:0010899, HP:0010916, HP:0003236

CaseAddInfo: homozygous

CasePreviousTesting: initial and confirmatory DBS, biochemical tests

CaseGenotypingMethod: mutation analyses

Variant: NM_000152.4(GAA):c.533G>A (p.Arg178His)

ClinVar: 554969; https://www.ncbi.nlm.nih.gov/clinvar/variation/554969/

gnomAD: 2.646e-05, http://exac.broadinstitute.org/variant/17-78078918-G-A

Patient25: Male, 15 years report, 2 years onset

CasePresentingHPOs: HP:0002527 (Falls)

HPOsFreeText: GAA activity 5.6% from leukocyte

CaseNotHPOs: HP:0002098, HP:0001324, HP:0001640, HP:0002240 (Respiratory distress, Muscle weakness, Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient14: Male, 59 years report, 40 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 6.9% from dried blood spot, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

Patient6: Male, 5 years report, 1 month onset

CasePresentingHPOs: HP:0001640, HP:0001324, HP:0002098 (Cardiomegaly, Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 6.8% from leukocyte, Wheelchair needed, Respiratory Assistance needed

CaseNotHPOs: HP:0002240 (Hepatomegaly)

NotHPOsFreeText: N/A

CaseAddInfo: IOPD

Patient20: Male, 22 years report, 12 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 11.6% from leukocyte, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

Patient24: Female, 17 years report, 15 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 4.6% from leukocyte, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

Patient33: Female, 24 years report, 3 year onset

CasePresentingHPOs: HP:0001324 (Muscle weakness)

HPOsFreeText: GAA activity 9.6% from leukocyte

CaseNotHPOs: HP:0002098, HP:0002240, HP:0001640 (Respiratory distress, Hepatomegaly, Cardiomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient12: Male, 19 years report, 13 years onset

CasePresentingHPOs: HP:0001324 (Muscle weakness)

HPOsFreeText: GAA activity 9.9% from leukocyte

CaseNotHPOs: HP:0002098, HP:0002240, HP:0001640 (Respiratory distress, Hepatomegaly, Cardiomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Case#: Subject number 11, male, 51 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0001324 (muscle weakness), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002153 (hyperkalemia)

CaseHPOFreeText:

CaseNotHPOs: HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0001638 (cardiomyopathy), HP:0002098 (respiratory distress), HP:0002094 (dyspnoea)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.21 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.-32-13T>C

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.2104C>T (p.Arg702Cys)

Variant 2 ClinVarID: 189040

Variant 2 CAid: CA274304

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 15, male, 58 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0001324 (muscle weakness), HP:0003546 (Exercise intolerance), HP:0002153 (hyperkalemia)

CaseHPOFreeText:

CaseNotHPOs: HP:0001252 (Hypotonia), HP:0002094 (dyspnoea), HP:0001638 (cardiomyopathy), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.31 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.-32-13T>C

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.655G>A (p.Gly219Arg)

Variant 2 ClinVarID: 189065

Variant 2 CAid: CA274334

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 14, female, 58 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0001324 (muscle weakness), HP:0001252 (Hypotonia)

CaseHPOFreeText:

CaseNotHPOs: HP:0003546 (Exercise intolerance), HP:0002094 (dyspnoea), HP:0001638 (cardiomyopathy), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002153 (hyperkalemia), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.33 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.-32-13T>C

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.-32-13T>C

Variant 2 ClinVarID: 4027

Variant 2 CAid: CA116606

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 19, male, 63 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0002153 (hyperkalemia), HP:0001324 (muscle weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0001638 (cardiomyopathy), HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002098 (respiratory distress), HP:0002094 (dyspnoea)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.47 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.2065G>A (p.Glu689Lys)

Variant 1 ClinVarID: 4030

Variant 1 CAid: CA116612

Variant 2: N/A

Variant 2 ClinVarID: N/A

Variant 2 CAid: N/A

Zygosity: Heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 17, male, 64 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0002153 (hyperkalemia), HP:0001324 (muscle weakness), HP:0003326 (Myalgia), HP:0002015 (dysphagia)

CaseHPOFreeText:

CaseNotHPOs: HP:0001252 (Hypotonia), HP:0001638 (cardiomyopathy), HP:0002098 (respiratory distress), HP:0003546 (Exercise intolerance), HP:0002094 (dyspnoea)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.54 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.-32-13T>C

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.875A>G (p.Tyr292Cys)

Variant 2 ClinVarID: 370577

Variant 2 CAid: CA16041886

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 12, male, 52 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0001324 (muscle weakness), HP:0002098 (respiratory distress)

CaseHPOFreeText:

CaseNotHPOs: HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0001638 (cardiomyopathy), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002153 (hyperkalemia), HP:0002094 (dyspnoea)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.48 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.-32-13T>C

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.1889-1G>A

Variant 2 ClinVarID: N/A

Variant 2 CAid: CA401369820

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Patient23: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1411_1414delGAGA (p.Glu471Profs)

ClinVar: 188874, https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/

gnomAD: 1.688e-05, http://exac.broadinstitute.org/variant/17-78083827-CGAGA-C

Variant2: NM_000152.4(GAA):c.2024_2026delACA (p.Asn675del)

ClinVar: 189006, https://www.ncbi.nlm.nih.gov/clinvar/variation/189006/

gnomAD: 2.105e-05, http://exac.broadinstitute.org/variant/17-78086806-CACA-C

Patient10: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.2105G>A (p.Arg702His)

ClinVar: 426278, https://www.ncbi.nlm.nih.gov/clinvar/variation/426278/

gnomAD: 6.695e-05, http://exac.broadinstitute.org/variant/17-78087081-G-A

Variant2: NM_000152.4(GAA):c.2297A>C (p.Tyr766Ser)

ClinVar: 420102, https://www.ncbi.nlm.nih.gov/clinvar/variation/420102/

gnomAD: 8.35e-06, http://exac.broadinstitute.org/variant/17-78090874-A-C

Patient11: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD, survived beyond 2yo, left ventricular mass index and left ventricular posterior wall thickness decreased during ERT. Able to raise head, sit without support, stand, walk alone

CaseNotHPOs: no significant respiratory problems during ERT

NotHPOsFreeText:

CaseAddInfo: homozygous, only patient to receive ERT treatment (rhGAA) every 2wks beginning at 5mo of age. ERT lasted for 90wks.

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Patient17: Female, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.4(GAA):c.2815_2816delGT (p.Val939Leufs)

ClinVar: 371481, https://www.ncbi.nlm.nih.gov/clinvar/variation/371481/

gnomAD: 1.653e-05, http://exac.broadinstitute.org/variant/17-78093082-CTG-C

Patient14: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1411_1414delGAGA (p.Glu471Profs)

ClinVar: 188874, https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/

gnomAD: 1.688e-05, http://exac.broadinstitute.org/variant/17-78083827-CGAGA-C

Variant2: NM_000152.3:c.2376_2377insCA

CAID: CA913184735, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184735

Patient6: Male, northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1115A>T (p.His372Leu)

ClinVar: 370483, https://www.ncbi.nlm.nih.gov/clinvar/variation/370483/

gnomAD: n/a

Variant2: NM_000152.3:c.2563G>C

CAID: CA401326195, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401326195

gnomAD: 0.00003188, http://gnomad.broadinstitute.org/variant/17-78092073-G-C

Patient1: Male, 26 years report, Iranian, Iran

CasePresentingHPOs: HP:0002098, HP:0001324, HP:0003236, HP:0002910 (Respiratory distress, Muscle weakness, Increased serum CK, Increased transaminases)

HPOsFreeText: GAA measurement from dried blood specimen at pH 3.8 was 0.19 nmol/spot * 21 h (ref 0.9-7.2) with acarbose and 0.89 nmol/spot * 21 h (ref 1.5-10) without acarbose and 4.40 nmol/spot * 21 h at pH 7.0 (ref 1.8-17.1), AST levels at 211 (ref 0-45), ALT levels at 294 (ref 5-40), CPK levels at 1925 (ref 25-200), FEV1 at 0.81, FEV1/FVC at 89.25

CaseAddInfo: Sibling of P2, Unsure of which second variant patient has since it is never specified

CaseIP-1: Female, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 0.45, GAA (MS/MS) enzyme activity at 0.01 umol/hr/L, Serum CK at 237 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.424_440del17 (p.Ser142Leufs*29)

CAID: CA658795228 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.424_440del17

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant3: NM_000152.4:c.1935C>A (p.Asp645Glu)

ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A

CaseAddInfo: Infantile Onset Pompe Disease, Nomenclature indicates Variant 2 and 3 are in cis

CaseLP2-8: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.01 umol/hr/L, Serum CK at 80 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant2: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

Variant3: NM_000152.4:c.1075+1G>T

CAID: CA401364842 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1075%2B1G%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis

CaseLP2-4: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.10 umol/hr/L, Serum CK at 66 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant2: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis and patient is homozygous for this allele, 1 other patient has the same genotype

CaseOPOPD-57: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.60 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.1958C>A (p.Thr653Asn)

CAID: CA8815557 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1958C%3EA

gnomAD: East Asian 2.548e-4, Overall 1.825e-5 http://gnomad.broadinstitute.org/variant/17-78086744-C-A

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype

CaseOPOPD-12: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.68 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant2: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

Variant3: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, Nomenclature shows that Variants 1 and 2 are in cis, 25 other patients share the same genotype

CaseIP2-10: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.09 umol/hr/L, Serum CK at 483 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant: NM_000152.4:c.1935C>A (p.Asp645Glu)

ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A

CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant

CaseLP2-3: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.42 umol/hr/L, Serum CK at 140 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.671G>A (p.Arg224Gln)

CAID: CA8814958 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.671G%3EA

gnomAD: African 8.060e-5, Overall 2.549e-5 http://gnomad.broadinstitute.org/variant/17-78079672-G-A

Variant2: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant3: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis

CasePDC-2: Male, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 0.84, MS/MS ennzyme activity at 1.34

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.3:c.693-5C>T

CAID: CA8814990 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.693-5C%3ET

gnomAD: East Asian 3.516e-4, Overall 3.900e-5 http://gnomad.broadinstitute.org/variant/17-78081351-C-T

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: Patient is either a carrier or has a pseudodeficency allele

CaseOPOPD-71: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.99 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2431dupC (p.Leu811Profs*?)

CAID: CA658795289 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.2431dupC

gnomAD: Not in gnomAD

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele

CaseOPTPD-77: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.61 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2014C>T (p.Arg672Trp)

ClinVar: 188773 https://www.ncbi.nlm.nih.gov/clinvar/variation/188773/

gnomAD: South Asian 3.355e-5, Overall 8.290e-6 http://gnomad.broadinstitute.org/variant/17-78086800-C-T

CaseAddInfo: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variant 2 is in cis with one copy

CaseOPOPD-9: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.68 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.671G>A (p.Arg224Gln)

ClinVar: CA8814958 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.671G%3EA

gnomAD: African 8.060e-5, Overall 2.549e-5 http://gnomad.broadinstitute.org/variant/17-78079672-G-A

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: One Pompe Mutation and One Pseudodeficency Mutation

CaseLP-4: Female, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 0.61, MS/MS ennzyme activity at 0.01

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant2: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

Variant3: NM_000152.4:c.1075+1G>T

CAID: CA401364842 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1075%2B1G%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Suspected Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis

CaseOPTPD-79: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.75 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2238G>C (p.Trp746Cys)

ClinVar: 265160 https://www.ncbi.nlm.nih.gov/clinvar/variation/265160/

gnomAD: European (Non-Finnish) 5.673e-4, Overall 3.083e-4 http://gnomad.broadinstitute.org/variant/17-78090815-G-C

CaseAddInfo: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variant 2 is in cis with one copy, 5 other patients have the same genotype

Patient1: Italian

CasePresentingHPOs:

HPOsFreeText: non-classic IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous

CasePMIDs:

CasePreviousTesting:

CaseGenotypingMethod: method not described

Variant: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)

ClinVar: 278911, https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: 0.00003188, https://gnomad.broadinstitute.org/variant/17-78085800-T-C

Patient3: Italian

CasePresentingHPOs:

HPOsFreeText: Juvenile onset Pompe

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting:

CaseGenotypingMethod: method not descibed

Variant1: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)

ClinVar: 278911, https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: 0.00003188, https://gnomad.broadinstitute.org/variant/17-78085800-T-C

Variant2: NM_000152.3:c.1333G>C

CAID: CA401366220, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401366220

gnomAD: n/a

Case#: Subject number 32, male, 39 years (diagnosis), 43 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0002098 (respiratory distress), HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 14, male, 41 years (diagnosis), 51 years (baseline visit), 45 years (ERT), 50 (ventilation)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness), HP:0002098 (respiratory distress)

CaseHPOFreeText: mechanical ventilation at Baseline Visit, mechanical ventilation at last visit

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea)

CaseNotHPOFreeText:

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 9, female, 29 years (diagnosis), 55 years (baseline visit), 48 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002870 (obstructive sleep apnea), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Case#: Subject number 35, female, 35 years (diagnosis), 35 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)

CaseHPOFreeText:

CaseNotHPOs: HP:0002098 (respiratory distress), HP:0002870 (obstructive sleep apnea), HP:0001324 (Muscle Weakness)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Patient5: male, Romanian

CasePresentingHPOs: HP:0003677, HP:0003236, HP:0003325, HP:0003418, HP:0008997

HPOsFreeText: CK > 10x increase, CK = 1500 U/L, reduced alpha-glucosidase activity

CaseNotHPOs: HP:0002093

CaseAddInfo: onset in middle age, enzyme activity also reduced in daughter

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.2066_2070dupAGCCG (p.Ala691Serfs)

ClinVar: 92471, https://www.ncbi.nlm.nih.gov/clinvar/variation/92471/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Patient7: female, Serbian

CasePresentingHPOs: HP:0003677, HP:0003236, HP:0003325

HPOsFreeText: CK < 10x increase

CaseNotHPOs: HP:0002093

CaseAddInfo: onset in middle age

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant 1: NM_000152.4(GAA):c.2269C>T (p.Gln757Ter)

ClinVar: 429727, https://www.ncbi.nlm.nih.gov/clinvar/variation/429727/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Patient18: female, White British

CasePresentingHPOs: HP:0003677, HP:0003236, HP:0003325, HP:0003701, HP:0003458, HP:0003715, HP:0030231

HPOsFreeText: CK > 10x increase, CK = 599 U/L. Vacuolated, degenerated, and atrophic fibers. Vacuole periphery showed abnormal immunoreactivity for desmin and p62. Z-band streaming of fibers, granular material accumulation. Treated with ERT. Normal to low alpha-glucosidase activity.

CaseNotHPOs: HP:0002093

NotHPOsFreeText: no evidence of glycogenosis

CaseAddInfo: onset after 50yo

CasePreviousTesting: same as group, muscle biopsy, NADH-tetrazolim reductase staining

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)

ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: 7.041e-05, http://exac.broadinstitute.org/variant/17-78078909-CT-C

Variant2: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Patient8: Female, Serbian, mid 70s

CasePresentingHPOs: HP:0003325

HPOsFreeText: Normal CK levels

CaseNotHPOs: HP:0003236, HP:0002093

CaseAddInfo: late onset

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.2051C>G

CAID: CA401370340, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401370340

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Patient6: Female, 19mo at diagnosis, 22.5mo at ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, moderate response to ERT, Pompe muscle pathology score = 3.1, Glycogen = 38.5 Vv(PAS + /mf)%, larger empty vacuoles = 25.9 Vv (LEV/mf)%, Autophagic vacuoles = 0,13%/mf

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)

ClinVar: 279811, https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: 1.663e-05, http://exac.broadinstitute.org/variant/17-78085800-T-C

Variant2: NM_000152.3:c.524_525del

CAID: CA913184732, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184732

gnomAD: n/a

Patient21: 68yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0003141, HP:0001513, HP:0020038

HPOsFreeText: GAA = 30%, BMI = 30.3, nucleo-capsular and subcortical white matter lacunes

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 30yr disease duration

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Patient8: 47yo

CasePresentingHPOs: HP:0003325, HP:0001513

HPOsFreeText: GAA = 5%, BMI = 30.8, Normal CTA and CT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 2yr disease duration, variants in cis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4(GAA):c.1551+1G>C

ClinVar: 554983, https://www.ncbi.nlm.nih.gov/clinvar/variation/554983/

gnomAD: n/a

Patient6: 47yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0020038

HPOsFreeText: GAA = 7%, BMI = 27.5, normal CT

CaseNotHPOs:

NotHPOsFreeText: No cardiovascular risk

CaseAddInfo: 14yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.3:c.2530_2541del

CAID: CA658795292, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795292

gnomAD: n/a

Patient18: 40yo

CasePresentingHPOs: HP:0003325

HPOsFreeText: GAA = 5%, smoker, BMI = 16.3, normal CTA and CT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 4yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.3:c.2530_2541del

CAID: CA658795292, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795292

gnomAD: n/a

Patient2: 76yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002315, HP:0004887, HP:0000822, HP:0002870, HP:0020038

HPOsFreeText: morning headaches, GAA = 13%, BMI = 23.6, right vertebral artery dominant, nucleo-capsular lacunes

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 33yr disease duration

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Patient9: 54yo

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002315, HP:0004887, HP:0003141, HP:0002870

HPOsFreeText: morning headache, GAA = 7%, smoker, BMI = 23.3, normal CTA, nucleo-capsular and subcortical white matter lacunes

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 29yr disease duration, variants in cis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4(GAA):c.1551+1G>C

ClinVar: 554983, https://www.ncbi.nlm.nih.gov/clinvar/variation/554983/

gnomAD: n/a

CaseLOPD-16: 2.5 weeks diagnosis

HPOsFreeText: GAA activity 2.5 (nmol · h−1 · mg−1), Mean percentage of normal 3.6%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Multiple interpretations of p.W746C possible, below is considered the most likely

Variant3: NM_000152.4:c.2238G>C (p.Trp746Cys)

ClinVar: 265160 https://www.ncbi.nlm.nih.gov/clinvar/variation/265160/

gnomAD: European (Non-Finnish) 5.673e-4, Overall 3.083e-4 http://gnomad.broadinstitute.org/variant/17-78090815-G-C

CaseAddInfo: Late Onset Pompe Disease, Nomenclature claims Variant 2 and 3 are in cis

CaseLOPD-10: 2 weeks diagnosis

HPOsFreeText: GAA activity 2.5 (nmol · h−1 · mg−1), Mean percentage of normal 3.6%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.517_519del (p.M173del)

CAID: CA891862611 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3:c.517_519del

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.710C>T (p.Ala237Val)

ClinVar: 4035 https://www.ncbi.nlm.nih.gov/clinvar/variation/4035/

gnomAD: South Asian 1.307e-4, Overall 1.992e-5 http://gnomad.broadinstitute.org/variant/17-78081373-C-T

CaseAddInfo: Late Onset Pompe Disease

CaseLOPD-13: 2 weeks diagnosis

HPOsFreeText: GAA activity 2.6 (nmol · h−1 · mg−1), Mean percentage of normal 3.7%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2051C>T (p.Pro684Leu)

ClinVar: 285821 https://www.ncbi.nlm.nih.gov/clinvar/variation/285821/

gnomAD: European (Non-Finnish) 1.631e-4, Overall 8.195e-5 http://gnomad.broadinstitute.org/variant/17-78087027-C-T

CaseAddInfo: Late Onset Pompe Disease

CaseLOPD-2: 2 weeks diagnosis

HPOsFreeText: GAA activity 3.2 (nmol · h−1 · mg−1), Mean percentage of normal 4.5%

GenotypingMethod: Newborn Screening Panels

Variant: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Late Onset Pompe Disease, Patient is homozygous for the above variant

CaseLOPD-6: 32 years diagnosis

HPOsFreeText: GAA activity 3.6 (nmol · h−1 · mg−1), Mean percentage of normal 5.1%

CaseNotHPOs: HP:0003236 (Increased serum CK)

GenotypingMethod: Newborn Screening Panels

Variant: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Late Onset Pompe Disease, Patient is homozygous for the above variant

CasePD/Pathogenic-5: 4 weeks diagnosis

HPOsFreeText: GAA activity 6.5 (nmol · h−1 · mg−1), Mean percentage of normal 9.1%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Variant3: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis

CaseIOPD-2: 10 days diagnosis

CasePresentingHPOs: HP:0003236, HP:0001638 (Increased serum CK, Cardiomyopathy)

HPOsFreeText: GAA activity 1.8 (nmol · h−1 · mg−1), Mean percentage of normal 1.2%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.854C>G (p.Pro285Arg)

ClinVar: 225114 https://www.ncbi.nlm.nih.gov/clinvar/variation/225114/

gnomAD: European (Non-Finnish) 1.148e-5, Overall 5.109e-6 http://gnomad.broadinstitute.org/variant/17-78081517-C-G

Variant2: NM_000152.4:c.2303C>T (p.P768L)

CAID: CA401324900 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3:c.2303C%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

CaseLOPD-5: 2 weeks diagnosis

HPOsFreeText: GAA activity 3.1 (nmol · h−1 · mg−1), Mean percentage of normal 4.4%

GenotypingMethod: Newborn Screening Panels

Variant: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Late Onset Pompe Disease, Patient is homozygous for the above variant

CaseLOPD-1: 3 weeks diagnosis

HPOsFreeText: GAA activity 3.2 (nmol · h−1 · mg−1), Mean percentage of normal 4.5%

GenotypingMethod: Newborn Screening Panels

Variant: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Late Onset Pompe Disease, Patient is homozygous for the above variant

CaseIOPD-4: 3 min diagnosis

CasePresentingHPOs: HP:0003236, HP:0001638 (Increased serum CK, Cardiomyopathy)

HPOsFreeText: GAA activity 0.6 (nmol · h−1 · mg−1), Mean percentage of normal 0.9%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.271G>A (p.Asp91Asn)

ClinVar: 4020 https://www.ncbi.nlm.nih.gov/clinvar/variation/4020/

gnomAD: European (Non-Finnish) 0.03291, Overall 0.02049 http://gnomad.broadinstitute.org/variant/17-78078656-G-A

Variant2: NM_000152.4:c.307T>G (p.Cys103Gly)

ClinVar: 92483 https://www.ncbi.nlm.nih.gov/clinvar/variation/92483/

gnomAD: European (non-Finnish) 7.874e-6, Overall 3.578e-6 http://gnomad.broadinstitute.org/variant/17-78078692-T-G

Variant3: NM_000152.4:c.1000G>T (p.Gly334Cys)

ClinVar: 284864 https://www.ncbi.nlm.nih.gov/clinvar/variation/284864/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease, Nomenclature claims Variant 1 and 2 are in cis

Case11HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 1.4 pmol/punch/hr, GAA activity at 33.2% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.1802C>A (p.Ser601Ter)

CAID: CA401369436 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1802C%3EA

gnomAD: Not in gnomAD

CaseAddInfo: Patient is homozygous for this variant

Case7HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 14 pmol/punch/hr, GAA activity at 58.3% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.525delT (p.Glu176Argfs)

ClinVar: 4033 https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: European (Non-Finnish) 1.880e-4, Overall 9.959e-5 https://gnomad.broadinstitute.org/variant/17-78078909-CT-C

CaseAddInfo:

Case13HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.5 mU/U hexosaminid, GAA activity at 17.5% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2482_2646del165 (p.Gly828_Asn882del) (Exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

CaseAddInfo: Patient is heterozygous for these variants

Case22HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 7 mU/U hexosaminidas, GAA activity at 25% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2608C>T (p.Arg870Ter)

ClinVar: 189009 https://www.ncbi.nlm.nih.gov/clinvar/variation/189009/

gnomAD: European (Non-Finnish) 4.888e-5, Overall 2.662e-5 https://gnomad.broadinstitute.org/variant/17-78092118-C-T

CaseAddInfo: Patient is compound heterozygous for these variants

Case#: Patient 4, Gender N/A, onset at 3-4 months. Died at 9 months, Southeast Asian

DiseaseAssertion:Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002094 HP:0001639. HP:0005165, HP:0001270 (Hypertrophic Cardiomyopathy, Dyspnea, Shortened PR interval, Motor delay )

CaseHPOFreeText: BVH, Died from dehydration (diarrhea)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: GAA activity in leukocytes was 0% of normal control value.

PCR of all exons was performed and subsequently subjected to capillary Sanger sequencing in both directions

Variant 1: c.1225dup (p.Asp409GlyfsX95)

ClinVar: N/A

CAID: CA923726362

gnomAD: N/A

Variant 2: c.2024_2026delACA (p.Asn675del)

ClinVar: 189006

CAID: CA274244

gnomAD: Highest population MAF = 0.0001106 (East asians)

ParentalGenotype: Father was carrier for Variant1 c.1226insG (p.Asp409GlyfsX95)

Mother was carrier of Variant 2 c.2024_2026delACA (p.Asn675del)

PreviouslyPublished: N/A

Case#: Patient 5, Gender N/A, Onset at 5-6 months. Death at 1.5 years of age, Southeast Asian

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002094 HP:0001639. HP:0005165, HP:0001270, HP:0001252, HP:0001714, HP:0002090

(Hypertrophic Cardiomyopathy, Dyspnea, Shortened PR interval, Motor delay, Muscular hypotonia, Ventricular hypertrophy, Pneumonia )

CaseHPOFreeText: Death from heart failure and pneumonia

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: GAA activity in leukocytes was 0% of normal control value.

PCR of all exons was performed and subsequently subjected to capillary Sanger sequencing in both directions

Variant 1: NM_000152.5(GAA):c.1538A>G (p.Asp513Gly)

ClinVar: 638014

CAID: CA401367134

gnomAD: N/A

ParentalGenotype: Both parents carried the .1538A>G (p.Asp513Gly) variant in the GAA gene. There was no parental consanguinity

PreviouslyPublished: N/A

Case14

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant: NM_000152.4:c.2560C>T (p.Arg854*)

ClinVar: 4034 https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/

gnomAD: African 1.891e-3, Overall 2.090e-4 http://gnomad.broadinstitute.org/variant/17-78092070-C-T

CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant, 6 more patients have the same genotype

Case50

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1210G>A (p.Asp404Asn)

CAID: CA8815234 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1210G%3EA

gnomAD: African 6.318e-5, Overall 3.223e-5 http://gnomad.broadinstitute.org/variant/17-78082511-G-A

Variant2: NM_000152.4:c.1924G>T (p.Val642Phe)

CAID: CA401369892 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1924G%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case5

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.546+2_5delTGGG

CAID: CA502402612 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.546%2B2_546%2B5delTGGG

gnomAD: European (Non-Finnish) 9.395e-6, Overall 4.224e-6 http://gnomad.broadinstitute.org/variant/17-78078930-CGGTG-C

Variant2: NM_000152.4:c.1650dupG (p.Thr551Aspfs*85)

CAID: CA8815425 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1650dupG

gnomAD: African 6.178e-5, Overall 3.992e-6 http://gnomad.broadinstitute.org/variant/17-78085789-T-TG

CaseAddInfo: Infantile Onset Pompe Disease, Patient has a sibling with the same genotype with Pompe

Case72

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease, 4 other patients have the same genotype

Case83

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.742delC (p.Leu248Profs*20)

CAID: CA658795236 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.742delC

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease

Case11

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2237G>A (p.Trp746*)

ClinVar: 280063 https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/

gnomAD: European (Non-Finnish) 8.834e-6, Overall 3.988e-6 http://gnomad.broadinstitute.org/variant/17-78090814-G-A

Variant2: NM_000152.4:c.437delT (p.Met146Argfs*7)

ClinVar: 554096 https://www.ncbi.nlm.nih.gov/clinvar/variation/554096/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case52

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2015G>T (p.Arg672Leu)

CAID: CA401370075 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.2015G%3ET

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.2783A>G (p.Tyr928Cys)

CAID: CA401327377 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.2783A%3EG

gnomAD: Not in gnomAD

CaseAddInfo: Juvenile Late Onset Pompe Disease

Case45

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.525delT (p.Glu176Argfs*45)

ClinVar: 4033 https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: European (Non-Finnish) 1.880e-4, Overall 9.959e-5 http://gnomad.broadinstitute.org/variant/17-78078909-CT-C

Variant2: NM_000152.4:c.1880C>T (p.Ser627Phe)

CAID: CA294896504 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1880C%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case62

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1548G>A (p.Trp516*)

ClinVar: 189025 https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/

gnomAD: European (Non-Finnish) 1.552e-5, Overall 7.079e-6 http://gnomad.broadinstitute.org/variant/17-78084636-G-A

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease, 1 person more with the same genotype

Case57

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1396_1397insG (p.Val466fs*39)

CAID: CA627699396 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1396_1397insG

gnomAD: South Asian 3.271e-5, Overall 4.003e-6 http://gnomad.broadinstitute.org/variant/17-78083807-A-AG

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease

Case9

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1826dupA (p.Tyr609*)

ClinVar: 189144 https://www.ncbi.nlm.nih.gov/clinvar/variation/189144/

gnomAD: European (Non-Finnish) 1.816e-5, Overall 8.159e-6 http://gnomad.broadinstitute.org/variant/17-78086447-T-TA

Variant2: NM_000152.4:c.2238G>A (p.Trp746*)

ClinVar: 370904 https://www.ncbi.nlm.nih.gov/clinvar/variation/370904/

gnomAD: African 4.011e-5, Overall 1.063e-5 http://gnomad.broadinstitute.org/variant/17-78090815-G-A

CaseAddInfo: Infantile Onset Pompe Disease

Case89

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.877G>A (p.Gly293Arg)

ClinVar: 4036 https://www.ncbi.nlm.nih.gov/clinvar/variation/4036/

gnomAD: Latino 5.704e-5, Overall 1.807e-5 http://gnomad.broadinstitute.org/variant/17-78081617-G-A

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease

Case31

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1438-1G>C

ClinVar: 189184 https://www.ncbi.nlm.nih.gov/clinvar/variation/189184/

gnomAD: African 1.150e-4, Overall 3.187e-5 http://gnomad.broadinstitute.org/variant/17-78084525-G-C

Variant2: NM_000152.4:c.1655T>C (p.Leu552Pro)

ClinVar: 279811 https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: European (Non-Finnish) 7.053e-5, Overall 3.188e-5 http://gnomad.broadinstitute.org/variant/17-78085800-T-C

CaseAddInfo: Infantile Onset Pompe Disease

Patient11: female, 49yo, adult onset

CasePresentingHPOs:

HPOsFreeText: LOPD, BMI = 21 / 19.4 / 20.2, WGMS = 2 / 2-3 / 3

CaseNotHPOs: HP:0002355

NotHPOsFreeText: did not require respiratory support

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.3:c.1291_1299del

CAID: CA658795248, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795248

gnomAD: n/a

Patient6: male, 50yo, adult onset

CasePresentingHPOs:

HPOsFreeText: LOPD, BMI = 26.3 / 26.6 / n-a, required use of wheelchair and BiPAP, WGMS = 3 / 4 / n-a

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4(GAA):c.1143delC (p.Ala382Leufs)

ClinVar: 370263, https://www.ncbi.nlm.nih.gov/clinvar/variation/370263/

gnomAD: 0.000004031, http://gnomad.broadinstitute.org/variant/17-78082353-AC-A

Patient7: male, 40yo, adult onset

CasePresentingHPOs:

HPOsFreeText: LOPD, BMI = 25.1 / 22.9 / 22.9, WGMS = 3 / 3 / 3

CaseNotHPOs: HP:0002355

NotHPOsFreeText: did not require respiratory support

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.3:c.1291_1299del

CAID: CA658795248, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795248

gnomAD: n/a

Patient10: 6yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA dosage = 40 EOW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous variants, 34day old at ERT

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Patient14: 3yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA dosage = 20 QW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous variants, 14days old at ERT start

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Patient3: 4yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA dosage = 40 EOW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 14days old at ERT start, stopped albuterol during 4th month of trial

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.3:c.1197_1208del

CAID: CA658795246, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795246

gnomAD: n/a

Patient12: 8yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA dosage = 20 EOW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 26days old at ERT start

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.4(GAA):c.1411_1414delGAGA (p.Glu471Profs)

ClinVar: 188874, https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/

gnomAD: 1.688e-05, http://exac.broadinstitute.org/variant/17-78083827-CGAGA-C

Case7: Female, 37 years onset, 38 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 40, GAA Activity at ~4.5 pmol/min/mg before ERT and ~5.5 after

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2237G>A (p.Trp746Ter)

ClinVar: 280063 https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/

gnomAD: European (Non-Finnish) 8.834e-6, Overall 3.988e-6 http://gnomad.broadinstitute.org/variant/17-78090814-G-A

CaseAddInfo: Late Onset Pompe Disease

Case2: Female, 42 years onset, 51 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 32, GAA Activity at ~10 pmol/min/mg before ERT and ~11 after

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1076-1G>C

CAID: CA401364879 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1076-1G%3EC

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case17: Female, 30 years onset, 39 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 41

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Paper does not specify what kind of mutation this is. Mentions only that it is a "Loss of transcript" mutation

Variant2: NM_000152.4:c.2331+1

ClinVar: N/A

gnomAD: N/A

CaseAddInfo: Late Onset Pompe Disease

Case12: Female, 48 years onset, 58 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 59, GAA Activity at ~17 pmol/min/mg before ERT and ~19 after

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1561G>A (p.Glu521Lys)

ClinVar: 4022 https://www.ncbi.nlm.nih.gov/clinvar/variation/4022/

gnomAD: South Asian 3.266e-5, Overall 3.980e-6 http://gnomad.broadinstitute.org/variant/17-78084749-G-A

CaseAddInfo: Late Onset Pompe Disease

Case#: Patient 16, female

CasePresentingHPOs: HP:0003325

CaseAddInfo: onset and diagnosis at 32yo

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

ClinVar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

VariantAllele2: NC_000017.11:g.(?80118193)(80118357_?)del

ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/

gnomAD: n/a

Case#: Patient 9, male

CasePresentingHPOs: HP:0003236, HP:0003325

CaseAddInfo: 48yo at onset, 52yo at diagnosis

Variant: NM_000152.4(GAA):c.-32-13T>G

ClinVar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Case#: Patient 12, male

CasePresentingHPOs: HP:0003236

CaseAddInfo: 42yo at onset, 46yo at diagnosis

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

ClinVar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

VariantAllele2: NM_000152.4(GAA):c.1438-2A>G

ClinVar: 526521, https://www.ncbi.nlm.nih.gov/clinvar/variation/526521/

gnomAD: n/a

Case#: Patient 3, female

CasePresentingHPOs: HP:0003236

CaseAddInfo: 29yo at onset, 39yo at diagnosis

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

ClinVar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

VariantAllele2: NM_000152.4(GAA):c.784G>A (p.Glu262Lys)

ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78081447-G-A

Case13: Male, Unknown years onset, Unknown years diagnosis, 39 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness)

CaseAddInfo: Late-Onset Pompe Disease

Case6: Female, 22 years onset, 23 years diagnosis, 37 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness)

CaseAddInfo: Late-Onset Pompe Disease

Case19: Male, 15 years onset, 15.5 years diagnosis, 15 years report

CasePresentingHPOs: HP:0003236 (Increased serum CK)

HPOsFreeText: Asymptomatic hyperCKemia

CaseAddInfo: Late-Onset Pompe Disease

Case9: Male, 21 years onset, 21.5 years diagnosis, 38 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747, HP:0003691 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness, Scapula alata)

CaseAddInfo: Late-Onset Pompe Disease

Case15: Male, 3.5 years onset, 5 years diagnosis, 16 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK)

CaseAddInfo: Late-Onset Pompe Disease

Case7: Male, 11 years onset, 16 years diagnosis, 27 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK)

CaseAddInfo: Late-Onset Pompe Disease

Case21: 12.5 years onset, 13 years diagnosis, 13 years report

CasePresentingHPOs: HP:0003236 (Increased serum CK)

HPOsFreeText: Asymptomatic hyperCKemia

CaseAddInfo: Late-Onset Pompe Disease, Gender reported as "W"

CaseC: Female, 2 months onset, 3 months diagnosis

CasePresentingHPOs: HP:0001270, HP:0003324, HP:0001638 (Motor delay, Generalized weakness, Cardiomyopathy)

HPOsFreeText: CRIM positive

CaseNotHPOs: HP:0100543, HP:0002540, HP:0004887 (Cognitive impairment, Inability to walk, Respiratory failure requiring assisted ventilation)

CaseAddInfo: Infantile-Onset Pompe Disease

Patient10: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.2105G>A (p.Arg702His)

ClinVar: 426278, https://www.ncbi.nlm.nih.gov/clinvar/variation/426278/

gnomAD: 6.695e-05, http://exac.broadinstitute.org/variant/17-78087081-G-A

Variant2: NM_000152.4(GAA):c.2297A>C (p.Tyr766Ser)

ClinVar: 420102, https://www.ncbi.nlm.nih.gov/clinvar/variation/420102/

gnomAD: 8.35e-06, http://exac.broadinstitute.org/variant/17-78090874-A-C

Patient16: Male, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.2662G>T (p.Glu888Ter)

ClinVar: 578595, https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/

gnomAD: 1.65e-05, http://exac.broadinstitute.org/variant/17-78092467-G-T

Variant2: NM_000152.3:c.1597T>G

CAID: CA401367282, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401367282

gnomAD: n/a

Patient24: Female, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: c.1151 + 2T > G no ClinVar or CAID, intronic position inside exon

Variant2: NM_000152.3:c.1562A>T

CAID: CA401367205, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401367205

gnomAD: 0.000003980, http://gnomad.broadinstitute.org/variant/17-78084750-A-T

Patient18: Male, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.4(GAA):c.796C>T (p.Pro266Ser)

ClinVar: 556117, https://www.ncbi.nlm.nih.gov/clinvar/variation/556117/

gnomAD: n/a

Case27: Male, 5 yr onset, 5 yr diagnosis, 10.1 yr report

HPOsFreeText: FVC z-score sitting -1.38 (84% pred), FVC z-score supine -2.55 (71% pred), 774 CK U/l, 1.7 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case24: Male, 2 yr onset, 2.9 yr diagnosis, 2.9 yr report

HPOsFreeText: Wheelchair used at 6 yr, Died of respiratory failure at 6 yr, FVC z-score sitting -5.29 (33% pred) at 5.7 yr, 1046 CK U/l, Deficient GAA activity (nmol/h/mg)^h from cultured fibroblasts

Case#: Subject number 20(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 204 U/L (60-305 U/L is normal), AST: 63 U/L (22-71 U/L is normal), ALT: 34 U/L (7-50 U/L is normal), BNP 65.4 pg/mL (0.0–100.0 pg/mL is normal)

glucosidase activity: GAA activity #1 was 0.88 micromole/L/h and GAA activity #2 (NBS) 0.77 in dried blood spots (>2.10 micromole/L/h is normal). 3.50 in confirmatory testing (>3.88 is normal).

Variant 1: NM_000152.5(GAA):c.-32-13T>G

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.-32-13T>G

Variant 2 ClinVarID: 4027

Variant 2 CAid: CA116606

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 26(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

glucosidase activity: GAA activity #2 (NBS) 1.01 in dried blood spots (>2.10 micromole/L/h is normal).

Variant 1: NM_000152.5(GAA):c.2238G>C

Variant 1 ClinVarID: 265160

Variant 1 CAid: CA8815665

Variant 2: NM_000152.5(GAA):c.2238G>C

Variant 2 ClinVarID: 265160

Variant 2 CAid: CA8815665

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 14(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 467 U/L (60-305 U/L is normal), AST: 166 U/L (20-64 U/L is normal), ALT: 73 U/L (12-42 U/L is normal), Hex4: 7.0 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 1.68 micromole/L/h and GAA activity #2 (NBS) 0.79 in dried blood spots (>2.10 micromole/L/h is normal). 2.40 in confirmatory testing (>3.88 is normal).

Variant 1: NM_000152.5(GAA):c.156_157delTC

Variant 1 ClinVarID: N/A

Variant 1 CAid: CA294886619

Variant 2: NM_000152.5(GAA):c.-32-13T>G

Variant 2 ClinVarID: 4027

Variant 2 CAid: CA116606

Zygosity: compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 1(I), male, 21 days (start of ERT), 31 months (report)

DiseaseAssertion: Infantile Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002870 (obstructive sleep apnea), HP:0001639 (hypertrophic cardiomyopathy), HP:0200128 (biventricular hypertrophy), HP:0030234 (Highly elevated creatine kinase)

CaseHPOFreeText: moderately to severely decreased left ventricular systolic wall motion, moderate hypertrophy of the left ventricle, severe right ventricular hypertrophy, requires BiPAP at night, patient receives physical, occupational, and speech therapies.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 923 U/L (60–305 U/L is normal), AST: 103 U/L (30–100 U/L is normal), BNP: 1080 pg/mL (0.0–100.0 pg/mL), Hex4: 24.7 mmol/mol Creatinine (≤20 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 0.65 micromole/L/h and GAA activity #2 (NBS) 0.22 in dried blood spots (>2.10 micromole/L/h is normal). 4.4 in confirmatory testing (>6.7 is normal).

Variant 1: NM_000152.5(GAA):c.759delC

Variant 1 ClinVarID: 837937

Variant 1 CAid: CA916082438

Variant 2: NM_000152.5(GAA):c.1551+1G>C

Variant 2 ClinVarID: 554983

Variant 2 CAid: CA401367167

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Patient11: Female, 39yo at diagnosis, 53yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:400, enzyme (μmol/g/h) = 0.41 (3-20), NIV required only after ERT began, mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 21yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1548G>A (p.Trp516Ter)

ClinVar: 189025, https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.2799+4A>G

ClinVar: 286228, https://www.ncbi.nlm.nih.gov/clinvar/variation/286228/

gnomAD: 8.319e-06, http://exac.broadinstitute.org/variant/17-78092608-A-G

Patient5: Female, 38yo at diagnosis, 40yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = neg, enzyme (μmol/g/h) = 0.8 (3-20)

CaseNotHPOs:

NotHPOsFreeText: NIV and mobility aid not used

CaseAddInfo: 26yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.3:c.482_483del

CAID: CA8814879, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA8814879

gnomAD: 1.729e-05, http://exac.broadinstitute.org/variant/17-78078864-TCC-T

Patient1: Female, 37yo at diagnosis, 38yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:800, Enzyme = 0.3 (3-20) μmol/g/h, NIV used before and after ERT, mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 23yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4:c.1040C>G

CAID: CA401364692, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1040C%3EG

gnomAD: n/a

Variant2: c.1559A > I believe this paper had a typo so I was unable to find this variant in both ClinVar and the allele registry

Patient2: Male, 40yo at diagnosis, 63yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies tire = 1:6400, enzyme (μmol/g/h) = 0.36 (3-20), NIV used before and after ERT

CaseNotHPOs:

NotHPOsFreeText: mobility aid not used

CaseAddInfo: 23yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.3:c.2135T>C

CAID: CA401370560, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.2135T%3EC

gnomAD: n/a