Variant: NM_000152.4:c.693-1G>C

CAID: CA401362948 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.693-1G%3EC

gnomAD: Not in gnomAD

VariantAddInfo: This variant was declared as novel and found in a patient, but no further information was given.

Variant: NM_000152.4:c.2334_2335dup (p.Pro779Argfs*3)

CAID: CA891862617 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.2334_2335dup

gnomAD: Not in gnomAD

VariantAddInfo: This variant was declared as novel and found in a patient, but no further information was given.

Case11: Female, 9 years onset, 6 years diagnosis (presymptomatic)

CaseAddInfo: Late-Onset Pompe Disease

Variant: NM_000152.4:c.1688A>T (p.Gln563Leu)

CAID: CA401368995 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1688A%3ET

gnomAD: Not in gnomAD

VariantAddInfo: This variant was declared as novel and found in a patient, but no further information was given.

Variant: NM_000152.4:c.1293_1326+57del (p.His432Ilefs*34)

CAID: CA891862614 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1293_1326%2B57del

gnomAD: Not in gnomAD

VariantAddInfo: This variant was declared as novel and found in a patient, but no further information was given.

Variant: NM_000152.3:c.799_803delinsA (p.Leu267Serfs*46)

CAID: CA891862613 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.799_803delinsA

gnomAD: Not in gnomAD

VariantAddInfo: This variant was declared as novel and found in a patient, but no further information was given.

CaseLP2-1: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.54 umol/hr/L, Serum CK at 72 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.1840A>G (p.Thr614Ala)

CAID: CA401369588 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1840A%3EG

gnomAD: Not in gnomAD

Variant3: NM_000152.4:c.2647-23delT

ClinVar: 557403 https://www.ncbi.nlm.nih.gov/clinvar/variation/557403/

gnomAD: East Asian 2.005e-3, Overall 1.432e-4 http://gnomad.broadinstitute.org/variant/17-78092425-CT-C

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

CaseIP2-5: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.13 umol/hr/L, Serum CK at 443 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1396G>T (p.Val466Phe)

CAID: CA401366509 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1396G%3ET

gnomAD: Not in gnomAD

Variant2: 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

CaseOPOPD-51: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.03 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.1822C>T (p.Arg608Ter)

CAID: CA8815488 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1822C%3ET

gnomAD: East Asian 5.103e-5, Overall 1.806e-5 http://gnomad.broadinstitute.org/variant/17-78086444-C-T

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele

CaseOPTPD-4: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.72 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.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: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variants 2 and 3 are in cis with each other and only one copy of 1

CaseIP-3: Female, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 0.42, MS/MS ennzyme activity at 0.10

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.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 1 and 2 are in cis and that the patient is homozygous for this allele

CaseOPOPD-48: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.02 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1508_1510del (p.Val503del)

CAID: CA627699576 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1508_1510del

gnomAD: East Asian 5.438e-5, Overall 3.980e-6 http://gnomad.broadinstitute.org/variant/17-78084592-ATGG-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 allele and One Pseudodeficency Mutation allele, 1 other has the same genotype

CaseOPOPD-53: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.80 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.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: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype

Case#: Subject number 25(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) 0.95 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 7(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 283 U/L (30-135 U/L is normal), Hex4: 2.6 mmol/mol Creatinine (≤3.0 mmol/mol Creatinine is normal)

glucosidase activity: GAA activity #1 was 1.05 micromole/L/h and GAA activity #2 (NBS) 0.19 in dried blood spots (>2.10 micromole/L/h is normal). 2.2 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.546 G>A

Variant 2 ClinVarID: 280955

Variant 2 CAid: CA8814895

Zygosity: compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 23(L)

DiseaseAssertion: Late Onset Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CK testing: 48 U/L (60-305 U/L is normal), AST: 73 U/L (22-71 U/L is normal), ALT: 28 U/L (7-50 U/L is normal), BNP 102.3 pg/mL (0.0–100.0 pg/mL is normal)

glucosidase activity: GAA activity #1 was 1.12 micromole/L/h and GAA activity #2 (NBS) 0.62 in dried blood spots (>2.10 micromole/L/h is normal). 2.5 in confirmatory testing (>3.88 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

Variant 3: NM_000152.5(GAA):c.2065G>A

Variant 3 ClinVarID: 4030

Variant 3 CAid: CA116612

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case24: Female, 48 years report

HPOsFreeText: 9 years of ERT completed, 6 Minute Walking Test at 180 meters, Forced Vital Capacity at 67%

GenotypingMethod: GAA Gene Sequencing

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.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

CaseAddInfo: Late Onset Pompe Disease

Case2: Female, 68 years report

HPOsFreeText: 5 years of ERT completed, 6 Minute Walking Test at 275 meters, Forced Vital Capacity at 116%

GenotypingMethod: GAA Gene Sequencing

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.1629C>G (p.Tyr543Ter)

CAID: CA401367368 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1629C%3EG

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case38: Male, 75 years report

HPOsFreeText: ERT not started, 6 Minute Walking Test at 246 meters

GenotypingMethod: GAA Gene Sequencing

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.1560C>G (p.Asn520Lys)

CAID: CA401367200 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1560C%3EG

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case34: Male, 46 years report

HPOsFreeText: ERT not started, 6 Minute Walking Test at 383 meters, Forced Vital Capacity at 73%

GenotypingMethod: GAA Gene Sequencing

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.1888+1G>A

CAID: CA8815511 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1888%2B1G%3EA

gnomAD: European (Non-Finnish) 9.843e-6, Overall 4.375e-6 http://gnomad.broadinstitute.org/variant/17-78086511-G-A

CaseAddInfo: Late Onset Pompe Disease

Case8: Male, 54 years report

HPOsFreeText: 8 years of ERT completed, 6 Minute Walking Test at 300 meters, Forced Vital Capacity at 33%

GenotypingMethod: GAA Gene Sequencing

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.1888+1G>A

CAID: CA8815511 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1888%2B1G%3EA

gnomAD: European (Non-Finnish) 9.843e-6, Overall 4.375e-6 http://gnomad.broadinstitute.org/variant/17-78086511-G-A

CaseAddInfo: Late Onset Pompe Disease

Case14: Female, 69 years report

HPOsFreeText: 9 years of ERT completed, 6 Minute Walking Test at 200 meters, Forced Vital Capacity at 51%

GenotypingMethod: GAA Gene Sequencing

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.118C>T (p.Arg40Ter)

ClinVar: 426593 https://www.ncbi.nlm.nih.gov/clinvar/variation/426593/

gnomAD: South Asian 6.561e-5, Overall 1.428e-5 http://gnomad.broadinstitute.org/variant/17-78078503-C-T

CaseAddInfo: Late Onset Pompe Disease

Case3: Female, 72 years report

HPOsFreeText: 4 years of ERT completed, 6 Minute Walking Test at 264 meters, Forced Vital Capacity at 56%

GenotypingMethod: GAA Gene Sequencing

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.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

CaseAddInfo: Late Onset Pompe Disease

Case5: Male, 57 years report

HPOsFreeText: 2 years of ERT completed, 6 Minute Walking Test at 461 meters, Forced Vital Capacity at 49%

GenotypingMethod: GAA Gene Sequencing

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.546+1G>T

CAID: CA401361913 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.546%2B1G%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case15: Female, 54 years report

HPOsFreeText: 8 years of ERT completed, 6 Minute Walking Test at 229 meters, Forced Vital Capacity at 39%

GenotypingMethod: GAA Gene Sequencing

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.1717A>C (p.Asn573His)

CAID: CA401369056 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1717A%3EC

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case#: Patient 7, Female, diagnosed at 3 months old (died at 15 months old), African American

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001638 (Cardiomyopathy)

CaseHPOFreeText: Previous to ERT patient did not required oxygen support. Patient needed Invasive ventilation at week 38 ERT until death 2 months later.

Previous to ERT and during it patient was unable to independently hold head or sit unsupported.

Previous to ERT NG tube feeds at age 3 months due to aspiration. During ERT patient used a GJ tube

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Variant: NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)

ClinVar: 4034

CAID: CA340130

gnomAD: Highest population MAF= 0.001891 (African)

ParentalGenotype:N/A

PreviouslyPublished: N/A

Case#: Patient 5, Female, 3.0 months old at diagnosis, African American

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0032988, HP:0001638

(Persistent head lag, Cardiomyopathy)

CaseHPOFreeText:

Previous to ERT patient was invasively ventilated, patient was unable to sit or roll over. NJ feeds started at age 3 months

Currently patient requires Oxygen and BiPAP at night. Stands with support and uses G tube for feeding.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: No GAA measurement

Variant: NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)

ClinVar: 4034

CAID: CA340130

gnomAD: Highest population MAF= 0.001891 (African)

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case79

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.-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, 3 other patients have the same genotype

Case23

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.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

Variant2: NM_000152.4:c.2236T>C (p.Trp746Arg)

ClinVar: 499293 https://www.ncbi.nlm.nih.gov/clinvar/variation/499293/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case44

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.1799G>T (p.Arg600Leu)

CAID: CA401369428 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1799G%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case26

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 code not given

Variant1: NM_000152.4: [del Exons 15–20]

ClinVar: N/A

gnomAD: N/A

Variant2: NM_000152.4:c.2012T>G (p.Met671Arg)

ClinVar: 92469 https://www.ncbi.nlm.nih.gov/clinvar/variation/92469/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case41

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.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

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

Patient9: Female, 9mo at diagnosis, 10mo at ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, poor response to ERT, Pompe muscle pathology score = 3.7, Glycogen = 43.1 Vv(PAS + /mf)%, larger empty vacuoles = 43.2 Vv (LEV/mf)%, Autophagic vacuoles = 0,31 %/mf

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous, biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.3:c.2431_2432insC

CAID: CA658795289, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795289

gnomAD: n/a

Patient3: Female, 2mo at diagnosis, 5mo at ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, moderate response to ERT, Pompe muscle pathology score = 1.4(a), 3.4(b), Glycogen = 19.5(a), 48.6(b) Vv(PAS + /mf)%, larger empty vacuoles = 10.2(a), 40.1(b) Vv (LEV/mf)%, Autophagic vacuoles = 0,27; 0 %/mf

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: c.1859 G > A this is the variant listed in the paper, but I believe this is a typo as both Clinvar and the allele registry have this position listed as 'C' rather than 'G'

NM_000152.3:c.1859C>A

CAID: CA401369666, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1859C%3EA

gnomAD: n/a

Variant2: 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: n/a

Patient1: Female, 3mo at diagnosis, 4mo at ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, moderate response to ERT, Pompe muscle pathology score = 2.2 (a), 3.3(b), Glycogen = 59.4(a), 63.8(b) Vv(PAS + /mf)%, larger empty vacuoles = 6.2(a), 18.3(b) Vv (LEV/mf)%, autophagic vacuoles = 0,25; 0 %/mf

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.104T>C

CAID: CA401360259, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401360259

gnomAD: n/a

Variant2: c.266 C > A This is the variant listed in the paper, but I believe this is a typo as both Clinvar and the allele registry have this position listed as 'G' rather than 'C'

NM_000152.4(GAA):c.266G>A (p.Arg89His)

ClinVar: 283219, https://www.ncbi.nlm.nih.gov/clinvar/variation/283219/#summary-evidence

gnomAD: 7.795e-05, http://exac.broadinstitute.org/variant/17-78078651-G-A

Case#: Subject number 13, male, 43 years (diagnosis), 47 years (baseline visit), 45 years (ERT), 44 (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 21, female, 20 years (diagnosis), 52 years (baseline visit), 45 years (ERT), 39 (age at ventilation)

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 8, female, 49 years (diagnosis), 59 years (baseline visit), 52 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 1, female, 38 years (diagnosis), 50 years (baseline visit), 47 years (ERT)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001324 (Muscle Weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0003236 (Elevated circulating creatine kinase concentration), HP:0002098 (respiratory distress), 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 31, male, 49 years (diagnosis), 51 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

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

CaseHPOFreeText:

CaseNotHPOs: HP:0002098 (respiratory distress), 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

Case#: Subject number 10, male, 13 years (diagnosis), 42 years (baseline visit), 39 years (ERT), 38 (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 19, female, 24 years (diagnosis), 35 years (baseline visit), 29 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

PMID: 31392188

Gene: GAA

Disease: Pompe disease

Inheritance: Autosomal recessive

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

Subject III-9: Female

CasePresentingHPOs:

HPOsFreeText: DBS neutral/acid = 36.0

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: asymptomatic, asserted carrier status

CasePMIDs:

CasePreviousTesting: DBS

CaseGenotypingMethod: GAA Genotyping

Variant: NM_000152.4(GAA):c.2560C>T (p.Arg854Ter)

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

gnomAD: 0.0002090, http://gnomad.broadinstitute.org/variant/17-78092070-C-T

PMID: 23787031

Gene: GAA

Disease: Pompe Disease

Inheritance: Autosomal Recessive

Patient4:

CasePresentingHPOs:

HPOsFreeText: Childhood onset Pompe

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting:

CaseGenotypingMethod: method not described

Variant1: NM_000152.3:c.1645G>C

CAID: CA401368767, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401368767

gnomAD: n/a

Variant2: NM_000152.3:c.692+1G>C

CAID: CA8814965, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA8814965

gnomAD: 0.000004171, https://gnomad.broadinstitute.org/variant/17-78079694-G-C

Patient7:

CasePresentingHPOs:

HPOsFreeText: classic IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous

CasePMIDs:

CasePreviousTesting:

CaseGenotypingMethod: method not described

Variant: NM_000152.4(GAA):c.1124G>T (p.Arg375Leu)

ClinVar: 283230, https://www.ncbi.nlm.nih.gov/clinvar/variation/283230/

gnomAD: 0.000008050, https://gnomad.broadinstitute.org/variant/17-78082336-G-T

Patient1: 40yo

CasePresentingHPOs:

HPOsFreeText: HyperCKemia, GAA = 4%, BMI = 25.8, normal CTA, temporo-insular lacunes

CaseNotHPOs:

NotHPOsFreeText: no cardiovascular risk factor

CaseAddInfo: 6yr 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

Patient15: 53yo

CasePresentingHPOs: HP:0002315, HP:0004887, HP:0000822, HP:0003141, HP:0002870, HP:0020038

HPOsFreeText: hyperCKema, morning headaches, GAA = 13%, BMI = 29.6, right ventricular artery dominant, Normal CT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 5yr disease duration, homozygous 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

Case#: Subject number 3, female, 9 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: Family member with PD

CasePresentingHPOs:

CaseHPOFreeText: Asymptomatic

CaseNotHPOs: HP:0002153 (hyperkalemia), HP:0001324 (muscle weakness), HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002098 (respiratory distress), HP:0002094 (dyspnoea), HP:0001638 (cardiomyopathy)

CaseNotHPOFreeText: no biopsy

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 0.15 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.1396_1397insG (p.Val466GlyfsTer?)

Variant 2 ClinVarID: ?

Variant 2 CAid: CA627699396

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 16, male, 59 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0002153 (hyperkalemia), HP:0002098 (respiratory distress), HP:0001324 (muscle weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0001252 (Hypotonia), HP:0001638 (cardiomyopathy), HP:0003326 (Myalgia), HP:0002015 (dysphagia), 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 0.17 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#: Patient 10, male, diagnosed 1995 (not given age of diagnosis), age 22 during study period

DiseaseAssertion: Pompe Disease

FamilyInfo: None given

CasePresentingHPOs: None given

CaseHPOFreeText: None given

CaseNotHPOs: None given

CaseNotHPOFreeText: None given

CasePreviousTesting: None given

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

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5:2228A>G

Variant 2 ClinVarID: 561162

Variant 2 CAid: CA401324753

ParentalGenotype: Not provided

Case#: Patient 8, male, diagnosed 2014 (not given age of diagnosis), age 19 during study period

DiseaseAssertion: Pompe Disease

FamilyInfo: None given

CasePresentingHPOs: None given

CaseHPOFreeText: None given

CaseNotHPOs: None given

CaseNotHPOFreeText: None given

CasePreviousTesting: None given

Variant 1: NM_000152.5:c.-32-13T>G (unclear variant nomenclature)

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5:c.1548G>A

Variant 2 ClinVarID: 189025

Variant 2 CAid: CA274281

ParentalGenotype: Not provided

Case#: Patient 6, female, diagnosed 2016 (not given age of diagnosis), age 30 during study period

DiseaseAssertion: Pompe Disease

FamilyInfo: None given

CasePresentingHPOs: None given

CaseHPOFreeText: Requires wheelchair for long distance movement

CaseNotHPOs: None given

CaseNotHPOFreeText: None given

CasePreviousTesting: None given

Variant 1: NM_000152.5:c.-32-13T>G (unclear variant nomenclature)

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5:c.525del (unclear variant nomenclature)

Variant 2 ClinVarID: 4033

Variant 2 CAid: CA220406

ParentalGenotype: Not provided

Case#: Patient 1, male, diagnosed 2000 (not given age), age 62 during study period

DiseaseAssertion: Pompe Disease

FamilyInfo: None given

CasePresentingHPOs: None given

CaseHPOFreeText: Requires B-pap at night

CaseNotHPOs: None given

CaseNotHPOFreeText: None given

CasePreviousTesting: None given

Variant 1: NM_000152.5:c.-32-13T>A

Variant 1 ClinVarID: N/A

Variant 1 CAid: CA913184742

Variant 2: NM_000152.5:c.1003G>A

Variant 2 ClinVarID: 972790

Variant 2 CAid: CA501005

ParentalGenotype: Not provided

Case#: Patient 15, female

CasePresentingHPOs: HP:0003236, HP:0003325

CaseAddInfo: 42yo at onset, 52yo 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.1927G>A (p.Gly643Arg)

ClinVar: 4023, https://www.ncbi.nlm.nih.gov/clinvar/variation/4023/

gnomAD: 5.884e-05, http://exac.broadinstitute.org/variant/17-78086713-G-A

Patient13: Male, 61yo

CasePresentingHPOs: HP:0003077, HP:0000822

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous, 13yr disease duration, ERT lasted 29mo

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

Case1: Female, 16 years onset, 18 years diagnosis, 38 years report, France

CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)

HPOsFreeText: Lost ambulation at 25 years, Started invasive ventilation at 25 years, Started ERT given every other week at a dose of 20 mg/kg at 29 years for 110 months, Peak Anti-rhGAA antibodies at 1:51,200, FVC at 0.43/11 (L / % expected), MIP at 17 (cm H2O), MEP at 19 (cm H2O), Time off ventilation increased from 10 to 40 (min/24 h), Total Motor Function Measure from 38 to 29

CaseNotHPOs: HP:0030148 (Heart murmur)

NotHPOsFreeText: No adverse reaction to ERT was recorded

CaseAddInfo: Late Onset Pompe Disease

CasePD/Pathogenic-7: 2 weeks diagnosis

HPOsFreeText: GAA activity 3.0 (nmol · h−1 · mg−1), Mean percentage of normal 4.2%

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.2167G>A (p.Val723Met)

CAID: CA8815635 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3:c.2167G%3EA

gnomAD: East Asian 6.213e-5, Overall 9.462e-6 http://gnomad.broadinstitute.org/variant/17-78087143-G-A

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

CasePD/Pathogenic-4: 2 weeks diagnosis

HPOsFreeText: GAA activity 5.0 (nmol · h−1 · mg−1), Mean percentage of normal 7.0%

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.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

Variant4: 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: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis, Nomenclature claims Variant 3 and 4 are in cis

CasePD/Pathogenic-3: 2 weeks diagnosis

HPOsFreeText: GAA activity 4.9 (nmol · h−1 · mg−1), Mean percentage of normal 6.9%

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.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

Variant4: 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: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis, Nomenclature claims Variant 3 and 4 are in cis

Patient19: Male, 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

Patient1: Male, 0.1mo at ERT start, 33mo at study end

CasePresentingHPOs:

HPOsFreeText: treated with 20mg/kg/2wk, patient had 18 infusion associated reactions

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.3:c.1460T>C

CAID: CA401366851, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401366851

gnomAD: n/a

Patient3: Male, 1.2mo at ERT start, 5.5yo at study end

CasePresentingHPOs:

HPOsFreeText: treated with 20mg/kg/2wks, patient had 27 infusion associated reactions

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1933G>T (p.Asp645Tyr)

ClinVar: 556386, https://www.ncbi.nlm.nih.gov/clinvar/variation/556386/

gnomAD: 0.000008250, http://gnomad.broadinstitute.org/variant/17-78086719-G-T

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

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

gnomAD: 0.00009959, http://gnomad.broadinstitute.org/variant/17-78078909-CT-C

PMID: 30778879

Gene: GAA

Patient 1

Variant1: NM_000152.3:c.1654del

CAID: CA658795262, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA658795262

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.2560C>T (p.Arg854Ter)

ClinVar: 4034, https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/#clinical-assertions

gnomAD: 0.0002090, http://gnomad.broadinstitute.org/variant/17-78092070-C-T

Patient 2 - homozygous

Variant: NM_000152.4(GAA):c.2560C>T (p.Arg854Ter)

ClinVar: 4034, https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/#clinical-assertions

gnomAD: 0.0002090, http://gnomad.broadinstitute.org/variant/17-78092070-C-T

Patient13: Female, Northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)

ClinVar: 194154, https://www.ncbi.nlm.nih.gov/clinvar/variation/194154/

gnomAD: n/a

Variant2: NM_000152.3:c.2411G>A

CAID: CA401325125, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401325125

gnomAD: n/a

Case6: Male, 25 years onset, 56 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 57, GAA Activity at ~10.5 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.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: Late Onset Pompe Disease

Case16: Female, 37 years onset, 49 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 50, GAA Activity at ~4 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.1465G>A (p.Asp489Asn)

ClinVar: 92465 https://www.ncbi.nlm.nih.gov/clinvar/variation/92465/

gnomAD: European (Finnish) 4.621e-5, Overall 1.195e-5 http://gnomad.broadinstitute.org/variant/17-78084553-G-A

CaseAddInfo: Late Onset Pompe Disease

Patient3: female, 62yo, adult onset

CasePresentingHPOs:

HPOsFreeText: LOPD, BMI = 19.4;19.7, WGMS = 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: c.2322_2323ins no ClinVar, no CAID

Patient8: female, 51yo, adult onset

CasePresentingHPOs:

HPOsFreeText: LOPD, BMI = 26.6 / 27.2 / n-a, required use of wheelchair, WGMS = 4 / 4 / n-a

CaseNotHPOs:

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_000152.4(GAA):c.877G>A (p.Gly293Arg)

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

gnomAD: 0.00001807, http://gnomad.broadinstitute.org/variant/17-78081617-G-A

Patient10: IOPD Group, 46days old

CasePresentingHPOs:

HPOsFreeText: LDH = 425 U/L, CK = 221 U/L, ALT = 41 U/L, AST = 61 U/L, Mann-Whitney Test = 2

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

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: 0.0001240, https://gnomad.broadinstitute.org/variant/17-78086721-C-A

Patient7: IOPD Group, 10days old

CasePresentingHPOs:

HPOsFreeText: LDH = 431 U/L, CK = 237 U/L, ALT = 23 U/L, AST = 58 U/L, Mann-Whitney Test = 2

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

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: 0.0001240, https://gnomad.broadinstitute.org/variant/17-78086721-C-A

Patient3: Female

CasePresentingHPOs: HP:0002194, HP:0001522

HPOsFreeText: ERT dosage = 20 mg/kg/2 w, CRIM negative

CaseNotHPOs: HP:0004887

NotHPOsFreeText:

CaseAddInfo: Symptom onset at 3d, diagnosis at 1mo, ERT at 2mo, ERT lasted for 1mo, died at 3mo.

CasePMIDs: 22252923, 27629047

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.3:c.1657C>T

CAID: CA401368835, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1657C%3ET

gnomAD: n/a

Patient12: Female

CasePresentingHPOs: HP:0002194, HP:0001522

HPOsFreeText: ERT dosage = 20mg/kg/2w, CRIM negative

CaseNotHPOs: HP:0004887

NotHPOsFreeText:

CaseAddInfo: Symptom onset at 4mo, diagnosis at 6mo, ERT at 8mo, ERT lasted for 0.5mo, died at 8.5mo

CasePMIDs: 22252923, 27629047

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.3:c.1657C>T

CAID: CA401368835, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3%3Ac.1657C%3ET

gnomAD: n/a

Patient10: male

CasePresentingHPOs: HP:0011471, HP:0001270, HP:0004887, HP:0002546, HP:0001371

HPOsFreeText: CRIM negative, Anti-rh GGA antibodies maximum titer = 1:25.600, immunomodulation = 14m, infusion associated reaction, tracheostomy, partial heart normalization

CaseNotHPOs:

CaseAddInfo: variants 1-3 in cis, but homozygous in trans, symptom onset at 2yo, diagnosis and ERT at 7yo. Died at 60mo due to cardiorespiratory failure.

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.1833_1839del

CAID: CA913184757, http://reg.clinicalgenome.org/redmine/projects/registry/gene_indel

gnomAD: n/a

Variant2: NM_000152.3:c.1846G>T

CAID: CA401369607, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401369607

gnomAD: n/a

Variant3: NM_000152.3:c.1847_1848insT

CAID: CA913184758, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184758

gnomAD: n/a

Patient20: Female

CasePresentingHPOs: HP:0004887, HP:0011471, HP:0001270, HP:0002546, HP:0000365

HPOsFreeText: CRIM positive, Anti-rh GGA antibodies maximum titer = 1:1.600, tracheostomy, partial heart normalization, moderate periventricular white matter abnormalities (hypomyelination)

CaseNotHPOs: HP:0002421, HP:0001371

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: homozygous variant in trans, symtom onset and diagnosis at 4yo, ERT at 5yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1564C>G (p.Pro522Ala)

ClinVar: 371277, https://www.ncbi.nlm.nih.gov/clinvar/variation/371277/

gnomAD: n/a

Patient6: female

CasePresentingHPOs: HP:0001270

HPOsFreeText: CRIM positive, partial heat normalization

CaseNotHPOs: HP:0004887, HP:0025156, HP:0001371

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: variants in trans, symptom onset at 4yo, diagnosis at 6yo, ERT at 10yo. Died due to infusion reaction with ERT.

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.3(GAA):c.742delC

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

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.896T>C (p.Leu299Pro)

ClinVar: 180144, https://www.ncbi.nlm.nih.gov/clinvar/variation/180144/

gnomAD: n/a

CaseD: Female, 9 months onset, 12 months diagnosis

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

HPOsFreeText: CRIM positive, Requires non-invasive ventilation during nighttime

CaseNotHPOs: HP:0100543, HP:0002540, HP:0001638 (Cognitive impairment, Inability to walk, Cardiomyopathy)

CaseAddInfo: Infantile-Onset Pompe Disease

Patient34: Male, 13 years report, 16 months onset

CasePresentingHPOs: HP:0002527, HP:0001640 (Falls, Cardiomegaly)

HPOsFreeText: N/A

CaseNotHPOs: HP:0002240 (Hepatomegaly)

NotHPOsFreeText: N/A

CaseAddInfo: LOPD

Patient17: Male, Caucasian

CasePresentingHPOs: HP:0003678, HP:0002093, HP:0003325, HP:0003701, HP:0003388, HP:0002111, HP:0003458

HPOsFreeText: normal CK levels, back muscle weakness, variability in muscle fibre diameter and glycogen accumulation. Slightly reduced alpha-glucosidase activity. Treated with ERT.

CaseNotHPOs: HP:0003236

CaseAddInfo: onset as a young adult, Pompe confirmed via Sanger Sequencing and DBS results.

CasePreviousTesting: same as group, EMG, muscle biopsy

CaseGenotypingMethod: same as group

Variant1: NM_000152.3:c.1192delC

CAID: CA628018372, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA628018372

gnomAD: n/a

Variant2: NM_000152.3:c.2716G>A

CAID: CA401326980, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401326980

gnomAD: n/a

Case#: P 6, Male, 2.8 months when started ERT (Died at 18.2 months old), ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 , HP:0001252 , HP:0003701, HP:0002090

(Hypertrophic cardiomyopathy, Muscular hypotonia, Proximal muscle weakness, Pneumonia)

CaseHPOFreeText: Pneumonia with deterioration was a complication during ERT. Also patient suffered progressive hypertrophic cardiomyopathy.

AR IV

Required ventilation

Best motor status was being able to sit

CaseNotHPOs: N/A

CaseNotHPOFreeText: Patient did not required tube feeding

CasePreviousTesting: CRIM status was unknown

Antibody titer was 1:84,000

Variant: NM_000152.5(GAA):c.915G>A (p.Gly305=)

ClinVar: 188478

CAID: CA198779

gnomAD: N/A

ParentalGenotype: Bothe the maternal an paternal allele of the GAA gene carried the variant c.915G>A (p.Gly305=)

PreviouslyPublished: N/A

Case#: Patient 8, Gender N/A, Onset at 1-2 months. Death at 13 months. Southeast Asian

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002240, HP:0001252, HP:0002789, HP:0001698 (Hepatomegaly, Muscular hypotonia, Tachypnea, Pericardial effusion)

CaseHPOFreeText: Hepatomegaly is mild, Pericardial effusion is mild, BHV, SDD

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal PR Interval

CasePreviousTesting: GAA activity in leukocytes was 1.46% of normal control value.

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

Variant: NM_000152.5(GAA):c.877G>A (p.Gly293Arg)

ClinVar: 4036

CAID: CA116622

gnomAD: Highest population MAF = 0.00005704 (Latino)

ParentalGenotype: Both parents were carriers of the variant c.877G>A (p.Gly293Arg)

PreviouslyPublished: N/A

Case#: Patient 3, Gender N/A, 5-6 months old when diagnosed.13 months when died, Southeast Asian

DiseaseAssertion: Pompe disease

FamilyInfo:

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

CaseHPOFreeText: Generalized Muscle weakness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

Variant1: NM_000152.5(GAA):c.1099T>C (p.Trp367Arg)

ClinVar:<br /> 555820

CAID: CA401364951

gnomAD: N/A

Variant2: NM_000152.5(GAA):c.1942G>A (p.Gly648Ser)

ClinVar: 188902

CAID: CA274102

gnomAD: Highest population MAF = 0.0003365 (South Asian)

ParentalGenotype: Father was carrier for Variant1 NM_000152.5(GAA):c.1099T>C (p.Trp367Arg)

Mother was carrier of Variant 2 NM_000152.5(GAA):c.1942G>A (p.Gly648Ser)

PreviouslyPublished: N/A

Patient2: 8yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA dosage = 20QW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 29days 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_000152.3:c.2842_2843insT

CAID: CA913184740, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184740

gnomAD: n/a

Case#: Patient 1

DiseaseAssertion: Pompe Disease

FamilyInfo: None given

CasePresentingHPOs: None

CaseHPOFreeText: None

CaseNotHPOs: None

CaseNotHPOFreeText: None

CasePreviousTesting: Single gene sequencing with Ion Torrent Persional Genome Machine

Glucosidase activity: 0.0 nmol 5MU/hr/mL

Variant 1: NM_000152.5:c.2065G>A

Variant 1 ClinVarID: 4030

Variant 1 CAid: CA116612

Variant 2: NM_000152.5:c.1726G>A

Variant 2 ClinVarID: 92467

Variant 2 CAid: CA145760

Variant 2: NM_000152.5:c.596A>G

Variant 3 ClinVarID: 92486

Variant 3 CAid: CA145785

Variant 2: NM_000152.5:c.668G>A

Variant 4 ClinVarID: 92488

Variant 4 CAid: CA145791

ParentalGenotype: Not provided

Case#: Subject number 6, male, 4 months (onset), 4 months (first admission)

DiseaseAssertion: Pompe disease

FamilyInfo: "no family history of neuromuscular disorders"

CasePresentingHPOs: HP:0004887 (respiratory failure requiring assisted ventilation), HP:0001639 (hypertrophic cardiomyopathy), HP:0001522 (death in infancy), HP:0002090 (pneumonia)

CaseHPOFreeText: infantile-onset, dysphagia at baseline

CaseNotHPOs:

CaseNotHPOFreeText: no tracheostomy, not on BiPAP

CasePreviousTesting: “GAA activity in peripheral blood leukocytes lower than normal”; on enzyme replacement therapy

Family 5 - Patients 5a and 5b

FamilyPresentingHPOs: HP:0009027, HP:0000467, HP:0003327, HP:0003691, HP:0002650, HP:0040081, HP:0100284

HPOsFreeText: Myotonic discharges in paraspinal, tibialis anterior, first dorsal interosseous, and biceps muscles, Myopathic muscle unit action potentials, 5b muscular pathology with Severe lysosomal vacuolar myopathy with prominent glycogen excess

FamilyNotHPOs: HP:0010628, HP:0002015, HP:0003306

Ethnicity: Iranian

ProbandLabel: 5a, male, 10yo at onset, 12yo at diagnosis

FamilyAddInfo: 5b (female) dx at 15 yo, 5a MRC sum score = 94, 5b MRC sum score = 91

FamilyPreviousTesting: Respiratory Evaluation: 5a FVC = 91%, 5b FVC = 106%, 5a CK = 1,202 U/L, 5b CK = 907 U/L, muscle pathology (examined only in 5b), DBS enzyme activity (with inhibition) for 5a = 0.5 μmol/L/h, for 5b = 0.6 μmol/L/h, NCS, EMG

FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening

Variant: NM_000152.3:c.1837T>G

ClinVar: n/a

CAID: CA401369569, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401369569

gnomAD: n/a

Case5HPOsFreeText: 10 mg/kg GAA treatment, GAA activity at 0.6 pmol/punch/hr, GAA activity at 6% 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

Unknown variant, likely a typo

Variant2: NM_000152.4:c.193G>T

ClinVar:

gnomAD:

CaseAddInfo:

Case9HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.6 pmol/punch/hr, GAA activity at 5.5% 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"

Variant: 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

CaseAddInfo: Patient is homozygous for this variant

Case8: Male, 1.5 yr onset, 2 yr diagnosis, 13.3 yr report

HPOsFreeText: FVC z-score sitting -0.91 (90% pred), FVC z-score supine -1.76 (80% pred), 93% MRC Scale, 1595 CK U/l, 16 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case#: Patient 4, Gender unknown, age unknown, ethnicity unknown

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0001638, HP:0003756

(Cardiomyopathy, Skeletal myopathy)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Sequence analysis of the GAA gene was performed in a CLIA and CAP certified laboratory. Cross Reactive Immune reaction was indeterminate in peripheral blood mononuclear cells (PBMCs)

Cross Reactive Immune reaction was not available in Dried blood spots.

Variant: NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)

ClinVar: 4034

CAID:CA340130

gnomAD: Highest population MAF= 0.001891 (African)

ParentalGenotype: N/A

Case#: Patient 2, Male, 71 year old, ethnicity unknown

DiseaseAssertion: Pompe disease

diagnosed at age 52 with SMA type III following an EMG reporting neurogenic changes and a muscle biopsy from a hamstring muscle that demonstrated denervation atrophy

FamilyInfo: N/A

CasePresentingHPOs: HP:0003701, HP:0003445

(Proximal muscle weakness, EMG:neuropathic changes

CaseHPOFreeText: Normal strength in the upper extremities with moderate weakness of hip flexion at 3/5, hip abduction 3–4/5, hip adduction 3–4/5, and hamstrings 4/5.

EMG showed myotonic discharges in the anterior tibialis, medial gastrocnemius, iliopsoas, tensor fasciae latae, and biceps brachii muscles.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Staining for PAS and acid phosphatase was normal.

Serum CK was 208 U/L (normal range 70–185)

CasePreviousTesting: GAA activity was 1.3pmol/punch/h (normal 10–49 pmol/punch/h) and he was found to have 2 heterozygous mutations

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

ClinVar: 4027

CAID: CA116606

gnomAD: Highest population MAF= 0.005541 (Ashkenazi Jewish)

Variant 2: NM_000152.5(GAA):c.1841C>A (p.Thr614Lys)

ClinVar: 167113

CAID: CA234050

gnomAD: Highest population MAF= 0.00004784 (European nin-Finnish)

ParentalGenotype:N/A

PreviouslyPublished:N/A

Case19: 1 mo (at biopsy), White

Case 19 (Level 2)

CasePreviousTesting: same as group. found 1.2 nmol/mg protein/18 h propionate incorporation, 1.0 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.655A>T (p.Asn219Tyr)

ClinVar: 1886

CAID: CA249731

gnomAD: 0.0001318 (European non-Finnish)

Variant2: NM_000255.3:c.1332+1delG

ClinVar: 554656

CAID: CA3846920

gnomAD: 0.000008828 (European non-Finnish)

CaseAddInfo: mut0 type, heterozygous mutations, unknown cis or trans

Case18: 2 mo (at biopsy), French Canadian

Case 18 (Level 2)

CasePreviousTesting: same as group. found 0.7 nmol/mg protein/18 h propionate incorporation, 0.7 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.655A>T (p.Asn219Tyr)

ClinVar: 1886

CAID: CA249731

gnomAD: 0.0001318 (European non-Finnish)

__

Variant2: NM_000255.3:c.1240delG (p.Glu414LysfsTer17)

ClinVar: n/a

CAID: CA3846936

gnomAD: 0.000008796 (European Non-Finnish)

CaseAddInfo: mut0 type. Variant 2 is novel. heterozygous mutations, unknown cis or trans.

Case17: 6 y (at biopsy), Black

Case 17 (Level 2)

CasePreviousTesting: same as group. found 0.6 nmol/mg protein/18 h propionate incorporation, 0.6 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.631_633delGAG (p.Glu211del)

ClinVar: n/a

CAID: CA913187321

gnomAD: n/a

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutations. Variant 1 is novel. MUT mutations are in trans- demonstrated by RT-PCR of mRNA. Additional variant found in MCEE gene (NM_032601.3:c.428G>A, ClinVar: 336936, CAID: CA1702575, gnomAD: 0.08102 (Latino)) MCEE variant is unlikely to be associated with patient's MMA.

Case16: 5 days (at biopsy), Lao/Thai/Mexican/Portugese

Case 16 (Level 2)

CasePreviousTesting: same as group. found 0.6 nmol/mg protein/18 h propionate incorporation, 0.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.581C>T (p.Pro194Leu)

ClinVar: n/a

CAID: CA364404418

gnomAD: n/a

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutation, unknown cis or trans

Case15: 3 wks (at biopsy), white

Case (Level 2)

CasePreviousTesting: same as group. found 0.5 nmol/mg protein/18 h propionate incorporation, 0.7 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.572C>A (p.Ala191Glu)

ClinVar: 203854

CAID: CA312777

gnomAD: 0.00006976 (European non-FInnish)

Variant2: NM_000255.3:c.754-2A>G

ClinVar: 552691

CAID: CA364402853

gnomAD: n/a

CaseAddInfo: variant 2 is a novel, splice site mutation. Heterozygous mutations, unknown cis or trans.

Case13: 21 y (at biopsy), English/Irish

Case (Level 2)

CasePreviousTesting: same as group. found 1.5 nmol/mg protein/18 h propionate incorporation, 1.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.572C>A (p.Ala191Glu)

ClinVar: 203854

CAID: CA312777

gnomAD: 0.00006976 (European non-FInnish)

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutation, unknown cis or trans

Case12: 6y (at biopsy), no ethnicity recorded

Case (Level 2)

CasePreviousTesting: same as group. found 0.5 nmol/mg protein/18 h propionate incorporation, 1.3 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.556A>G (p.Met186Val)