Case18 Female, 9.9yo report, Ethnicity: Austrian

CasePresentingHPOs HP:0003571, HP:0008872, HP:0001531, HP:0001254, HP:0002789, HP:0002045

(propionicacidemia, feeding difficulties in infancy, failure to thrive in infancy, lethargy, tachypnea, hypothermia)

HPOsFreeText feeding difficulties, failure to thrive, lethargy, tachypnea, hypothermia, exanthema (5do). Scored 55 on Snijders-Omen Test for IQ

CaseNotHPOs n/a

CasePreviousTesting Diagnosed by selective metabolic screening. PCC activity in patient lymphoblasts was 0.4% of control.

Variant NM_000532.4:c.1199-2A>G (Gly400fs), homozygous

ClinVar n/a

CAID CA354648962

gnomAD not in gnomAD

CaseAddInfo parents not consanguineous

CasePMIDs n/a

Case54 Male, 7.3yo report, Ethnicity: Turkish

CasePresentingHPOs HP:0003571, HP:0008872, HP:0002013, HP:0008947, HP:0002789, HP:0002045

(propionicacidemia, feeding difficulties in infancy, vomiting, infantile hypotonia, tachypnea, hypothermia)

HPOsFreeText feeding difficulties, vomiting, hypotonia, tachypnea, hypothermia(3do). 55 IQ on Culture Free Test

CaseNotHPOs n/a

CasePreviousTesting Diagnosis by selective metabolic screen. Patient fibroblasts had 1.5% PCC activity of control

Variant NM_000532.4(PCCB):c.990dupT (p.Glu331Terfs), homozygous

ClinVar 167423

gnomAD MAF= 0.001001(African), no homozygotes

CaseAddInfo parental consanguinity

CasePMIDs n/a

Case35 Male, 7.1yo report, Ethnicity: Syrian

CasePresentingHPOs HP:0003571, HP:0002789

(propionicacidemia, tachypnea)

HPOsFreeText tachypnea(6do). 55 IQ on Culture Free Test

CaseNotHPOs n/a

CasePreviousTesting Diagnosis by NBS. Patient fibroblasts had 1.5% PCC activity of control.

Variant NM_000532.4:c.1313C>T (p.Ala438Val), homozygous

ClinVar n/a

CAID CA354649295

gnomAD not in gnomAD

CaseAddInfo no parental consanguinity

CasePMIDs n/a

Case34 female, 5.5yo report, Ethnicity: German

CasePresentingHPOs HP:0003571, HP:0012523, HP:0001531, HP:0002791, HP:0001944

(propionicacidemia, oral aversion, failure to thrive in infancy, bradypnea, dehydration)

HPOsFreeText feeding refusal, failure to thrive, bradypnea, dehydration(2do). 55 IQ on Culture Free Test

CaseNotHPOs n/a

CasePreviousTesting Diagnosed on newborn screen. PCC activity in patient fibroblasts was 0.9% of control

Variant NM_000532.4:c.483dup (p.Gly162TrpfsTer?), homozygous

ClinVar n/a

CAID to register

gnomAD not in gnomAD

CaseAddInfo no parental consanguinity

CasePMIDs n/a

Case32 Male, 13.6yo report, Ethnicity: Turkish

CasePresentingHPOs HP:0003571, HP:0001531, HP:0008947, HP:0002789, HP:0001259, HP:0002045, HP:0002240

(proprionicacidemia, failure to thrive in infancy, infantile hypotonia, tachypnea, coma, hypothermia, hepatomegaly)

HPOsFreeText feeding difficulties, failure to thrive, hypotonia, tachypnea, coma, hypothermia, hepatomegaly(4do). 57 IQ on Snijders-Omen Test

CaseNotHPOs n/a

CasePreviousTesting Diagnosed by newborn screening. Patient fibroblasts had 0.7% PCC activity of controls.

Variant NM_000532.4:c.613G>T (p.Val205Phe), homozygous

ClinVar n/a

CAID CA354641901

gnomAD not in gnomAD

CaseAddInfo parental consanguinity

CasePMIDs n/a

FamilyLabel 29/30 Fam

Family29/30PresentingHPOs HP:0003571, HP:0002789

(Propionicacidemia, Tachypnea)

HPOsFreeText n/a

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Iraqi

Race n/a

Family29/30PreviousTesting n/a

ProbandLabel 29

Variant NM_000532.4:c.183+2T>C (p.=), homozygous

ClinVar n/a

CAID CA354738149

gnomAD not in gnomAD

FamilyAddInfo parental consanguinity

FamilyPMIDs n/a

Case23 Female, 5.2yo report, Ethnicity: Russian

CasePresentingHPOs HP:0003571, HP:0012523, HP:0001531, HP:0001944, HP:0001259, HP:0001250

(propionicacidemia, oral aversion, failure to thrive in infancy, dehydration, coma, seizures)

HPOsFreeText feeding refusal, failure to thrive, dehydration, coma, seizures(7do). 55 IQ on Culture-Free-Test.

CaseNotHPOs n/a

CasePreviousTesting Diagnosis by newborn screening. PCC activity in patient fibroblasts was 0.5% of control.

Variant NM_000532.4:c.803T>G (p.Leu268Trp), homozygous

ClinVar n/a

CAID CA354644558

gnomAD not in gnomAD

CaseAddInfo no parental consanguinity

CasePMIDs n/a

FamilyLabel 38/39 Fam

Family38/39PresentingHPOs n/a

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Turkish

Race n/a

Family38/39PreviousTesting Diagnosed by selective metabolic screen

ProbandLabel 38

Variant NM_000532.4(PCCB):c.1534C>T (p.Arg512Cys), homozygous

ClinVar 38879

gnomAD MAF= 0.00005440(East Asian), no homozygotes

FamilyAddInfo parental consanguinity

FamilyPMIDs n/a

Case8 Male, 9.8yo report, Ethnicity:Turkish

CasePresentingHPOs HP:0012523, HP:0001508, HP:0002013, HP:0008947, HP:0002789, HP:0002045, HP:0002014, HP:0003571

(propionicacidemia, oral aversion, failure to thrive, vomiting, infantile hypotonia, tachypnea, hypothermia, diarrhea)

HPOsFreeText feeding refusal, failure to thrive, vomiting, hypotonia, tachypnea, hypothermia, diarrhea (4do). 73 IQ on Culture Free Test.

CaseNotHPOs n/a

CasePreviousTesting Diagnosed by selective metabolic screening

Variant NM_000532.4:c.429+3_6delAAGT (p.Asp125_Lys143del), homozygous

ClinVar n/a

CAID to register

gnomAD not in gnomAD

CaseAddInfo parental consanguinity

CasePMIDs n/a

Case27 Male, 3do onset, Ethnicity: Turkish

CasePresentingHPOs HP:0003571, HP:0008872, HP:0008947, HP:0002789, HP:0002789

(propionicacidemia, feeding difficulties in infancy, infantile hypotonia, tachypnea)

HPOsFreeText feeding difficulties, hypotonia, somnolence, tachypnea (3do)

CaseNotHPOs n/a

CasePreviousTesting Diagnosis by selective metabolic screen.

Variant NM_000532.4:c.1309G>A (p.Gly437Ser), homozygous

ClinVar n/a

CAID CA354649286

gnomAD MAF= 0.00008674(Latino), no homozygotes

CaseAddInfo parental consanguinity

CasePMIDs n/a

Case22 Male, 13.5yo report, Ethnicity: German

CasePresentingHPOs HP:0003571, HP:0008872, HP:0001531, HP:0002240

(propionicacidemia, feeding difficulties in infancy, failure to thrive in infancy, hepatomegaly)

HPOsFreeText feeding difficulties, failure to thrive, hepatomegaly(4do), 55 IQ on Snijders-Omen Test

CaseNotHPOs n/a

CasePreviousTesting Diagnosed by selective metabolic screening. PCC activity was 0.81 in patient fibroblasts vs control.

Variant NM_000532.4:c.1218_1231delins12 (p.Gly406fs), homozygous

ClinVar n/a

CAID link to register the deletion, but the insertion is not described

gnomAD not in gnomAD

CaseAddInfo no parental consanguinity

CasePMIDs n/a

Case21 Female, 8.8yo report, Ethnicity: Italian

CasePresentingHPOs HP:0003571, HP:0012523, HP:0002013, HP:0008947, HP:0001259, HP:0002789

(propionicacidemia, oral aversion, vomiting, infantile hypotonia, coma, seizures, tachypnea)

HPOsFreeText feeding refusal, vomiting, hypotonia, coma, seizures, tachypnea, exanthema (14do). 55 IQ on Snijders-Omen Test.

CaseNotHPOs n/a

CasePreviousTesting Diagnosed by selective metabolic screen. PCC activity in patient fibroblasts was 1.1% of control.

Variant NM_000532.4(PCCB):c.562G>A (p.Gly188Arg), homozygous

ClinVar 558327

gnomAD MAF= 0.00006152(African), no homozygotes

CaseAddInfo no parental consanguinity

CasePMIDs n/a

CaseF-22 male, 5do onset, Ethinicity: North Indian, Muslim

CasePresentingHPOs HP:0006846, HP:0001254, HP:0011968, HP:0001250, HP:0001987, HP:0001946, HP:0045045, HP:0003571

(Acute encephalopathy, Lethargy, Poor feeding, Seizures, Hyperammonemia, Ketosis, Elevated acylcarnitines, Propionicacidemia)

HPOsFreeText Serum ammonia 700micromolar

CaseNotHPOs n/a

CasePreviousTesting Also screened for variants in PCCA

Variant NM_000532.4(PCCB):c.183+5G>A

ClinVar 217896

gnomAD MAF= 0.00003328(South Asian), no homozygotes

CaseAddInfo consanguineous, no abnormality in family history noted

CasePMIDs n/a

CaseF-15 female, 1yo onset, Ethnicity: North Indian, Hindu

CasePresentingHPOs HP:0006846, HP:0001254, HP:0011968, HP:0002098, HP:0002013, HP:0001942, HP:0001943, HP:0003571

(Acute encephalopathy, Lethargy, Poor feeding, Respiratory distress, Vomiting, Metabolic acidosis, Hypoglycemia, Propionicacidemia)

HPOsFreeText Ketones present, acycarnitines 6.2(normal <3.6nmol/mL), died after acute crisis(1yo)

CaseNotHPOs n/a

CasePreviousTesting Also screened for variants in PCCA

Variant NM_000532.4(PCCB):c.493C>T (p.Arg165Trp)

ClinVar 217894

gnomAD MAF= 0.00001456(European(non-Finnish), no homozygotes

CaseAddInfo nonconsanguineous, no abnormality in family history noted

CasePMIDs n/a

CaseF-4 female, 2mo onset, Ethnicity: Southern Indian, Muslim

CasePresentingHPOs HP:0006846, HP:0001254, HP:0001987, HP:0002154, HP:0045045, HP:0003571

(Acute encephalopathy, Lethargy, Hyperammonemia, Elevated blood glycine, Elevated acylcarnitines, Propionicacidemia)

CaseNotHPOs n/a

CasePreviousTesting Also screened for variants in PCCA

Variant NM_000532.4(PCCB):c.1540C>T (p.Arg514Ter)

ClinVar 217893

gnomAD MAF=0.00005015(South Asian), no homozygotes

CaseAddInfo consanguineous, abnormality in family history noted

CasePMIDs n/a

CaseF-25 female, 4do onset, Ethnicity: North Indian, Muslim

CasePresentingHPOs HP:0006846, HP:0001254, HP:0002098, HP:0001942, HP:0045045, HP:0003571

(Acute encephalopathy, Lethargy, Respiratory distress, Poor feeding, Metabolic acidosis, Elevated acylcarnitines, Propionicacidemia)

HPOsFreeText Serum ammonia 86.4micromolar

CaseNotHPOs n/a

CasePreviousTesting Also screened for variants in PCCA

Variant NM_000532.4(PCCB):c.1498+2T>C

ClinVar 217895

gnomAD not in gnomAD

CaseAddInfo consanguineous, no abnormalities in family history noted

CasePMIDs n/a

CaseF-2 male, 14mo onset, Ethnicity: North Indian, Hindu

CasePresentingHPOs HP:0001263, HP:0003571

(Developmental delay, Propionicacidemia)

HPOsFreeText normal plasma amino acids, acylcarnitines 13.9(normal <3.6nmol/mL), normal development by 6.5 years

CaseNotHPOs HP:0001942, HP:0001987

(Metabolic acidosis, Hyperammonemia)

CasePreviousTesting Also screened for variants in PCCA

Variant NM_000532.4(PCCB):c.1210G>A (p.Glu404Lys)

ClinVar 217891

gnomAD MAF= 0.00003266(South Asian), no homozygotes

CaseAddInfo nonconsanguineous, no abnormality in family history noted

CasePMIDs n/a

CaseF-3 Male, 5do onset, Ethnicity: North Indian, Hindu

CasePresentingHPOs HP:0006846, HP:0001254, HP:0011968, HP:0001250, HP:0002098, HP:0001942, HP:0001987, HP:0003571, HP:0002154, HP:0010910, HP:0012026

(Acute encephalopathy, Lethargy, Poor feeding, Seizures, Respiratory distress, Metabolic acidosis, Hyperammonemia, Propionicacidemia, Elevated blood glycine, Elevated blood valine, Elevated blood ornithine)

HPOsFreeText Serum ammonia 143micromolar, acycarnitines 31.7(normal <3.6nmol/mL)

CaseNotHPOs n/a

CasePreviousTesting Also screened for variants in PCCA

Variant NM_000532.4(PCCB):c.183+5G>A

ClinVar 217896

gnomAD MAF= 0.00003328(South Asian), no homozygotes

CaseAddInfo nonconsanguineous, abnormality in family history noted

CasePMIDs n/a

Case1752 Caucasian

CasePresentingHPOs HP:0003571 (Propionicacidemia)

CaseNotHPOs n/a

CasePreviousTesting none reported

Variant 1. NM_000532.4(PCCB):c.1218_1231delGGGCATCATCCGGCinsTAGAGCACAGGA (p.Gly407Argfs), 2. NM_000532.4:c.1222del (p.Ile408SerfsTer?)

ClinVar 1.38875, 2. n/a

CAID 2. unregistered

gnomAD 1. not in gnomAD

CaseAddInfo parents NOT tested, phase unknown

CasePMIDs n/a

Case2267(g) Caucasian, Hispanic

CasePresentingHPOs HP:0003571 (Propionicacidemia)

CaseNotHPOs n/a

CasePreviousTesting none reported

Variant NM_000532.4(PCCB):c.1218_1231delGGGCATCATCCGGCinsTAGAGCACAGGA (p.Gly407Argfs)

ClinVar 38875

gnomAD not in gnomAD

CaseAddInfo parents tested heterozygous

CasePMIDs n/a

Case467 Caucasian

CasePresentingHPOs HP:0003571 (Propionicacidemia)

CaseNotHPOs n/a

CasePreviousTesting none reported

Variant 1. NM_000532.4(PCCB):c.1218_1231delGGGCATCATCCGGCinsTAGAGCACAGGA (p.Gly407Argfs), 2. NM_000532.4:c.1222del (p.Ile408SerfsTer?)

ClinVar 1.38875, 2. n/a

CAID 2. unregistered

gnomAD 1. not in gnomAD

CaseAddInfo parents NOT tested, phase unknown

CasePMIDs n/a

Variant NM_000532.4(PCCB):c.1228C>T (p.Arg410Trp)

ClinVar 12011

gnomAD MAF=0.00006533(South Asian), no homozygotes

CaseJ 113 Japanese

CasePresentingHPOs HP:0003571 (Propionicacidemia)

CaseNotHPOs n/a

CasePreviousTesting none reported

Variant NM_000532.4(PCCB):c.1228C>T (p.Arg410Trp)

ClinVar 12011

gnomAD MAF=0.00006533(South Asian), no homozygotes

CaseAddInfo parents tested heterozygous

CasePMIDs n/a

FamilyLabel Unknown Family

FamilyUnknownPresentingHPOs HP:0003571 (Propionicacidemia)

FamilyNotHPOs n/a

CountryOrigin Japan

Ethnicity n/a

Race n/a

FamilyUnknownPreviousTesting none reported

ProbandLabel J 146

Variant NM_000532.4(PCCB):c.1228C>T (p.Arg410Trp)

ClinVar 12011

gnomAD MAF=0.00006533(South Asian), no homozygotes

FamilyAddInfo sibling J 171 genotyped, no further info for either case

FamilyLabel pccC Family

FamilypccCPresentingHPOs HP:0003571 (Propionicacidemia)

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity n/a

Race Caucasian

FamilypccCPreviousTesting none reported

ProbandLabel 572

Variant NM_000532.4(PCCB):c.1218_1231delGGGCATCATCCGGCinsTAGAGCACAGGA (p.Gly407Argfs)

ClinVar 38875

gnomAD not in gnomAD

FamilyAddInfo sibling 756 also genotyped, no further info for either case

based on the numbering from the C>T change that was in ClinVar and looking at Figure 4, this deletion takes place at c.12222.

Variant NM_000532.4:c.1222del (p.Ile408SerfsTer?)

ClinVar n/a

CAID unregistered

Going off of the numbering from the C>T variant in ClinVar and Figure 4, this other ClinVar entry matches exactly.

Variant NM_000532.4(PCCB):c.1218_1231delGGGCATCATCCGGCinsTAGAGCACAGGA (p.Gly407Argfs)

ClinVar 38875

gnomAD not in gnomAD

CasePA008 10mo report, Taiwan

CasePresentingHPOs HP:0001987, HP:0001943, HP:0011342, HP:0003571

(Hyperammonemia, Hypoglycemia, mild global developmental delay, propionicacidemia)

HPOsFreeText hyperammonemia and hypoglycemia for a few days after birth. Showed mild developmental delay at 10 months old

CaseNotHPOs n/a

CasePreviousTesting coding regions and flanking areas of PCCA also analyzed with PCR and Sanger

Variant 1. NM_000532.4(PCCB):c.1301C>T (p.Ala434Val), 2. NM_000532.4:c.-4156_183+3713del

ClinVar 1. 554490, 2. n/a

CAID 2. n/a

gnomAD 1. MAF=0.0003510(East Asian), no homozygotes, 2. n/a

CaseAddInfo n/a

CasePMIDs n/a

CasePA007 4do onset, Taiwan

CasePresentingHPOs HP:0003571, HP:0011968, HP:0002098, HP:0001290, HP:0002240, HP:0002789, HP:0004372, HP:0001987, HP:0003811

(propionicacidemia, poor feeding, respiratory distress, hypotonia, hepatomegaly, tachypnea, disturbed consciousness, hyperammonemia, neonatal death)

HPOsFreeText poor activity and other phenotypes presented at 4 days old. Died at 6 days old

CaseNotHPOs n/a

CasePreviousTesting coding regions and flanking areas of PCCA also analyzed with PCR and Sanger

Variant 1. NM_000532.4(PCCB):c.1301C>T (p.Ala434Val),2. NM_000532.4(PCCB):c.838dup (p.Leu280Profs)

ClinVar 1. 554490, 2. 552435

gnomAD 1. MAF= 0.0003510(East Asian), no homozygotes, 2. not in gnomAD

CaseAddInfo n/a

CasePMIDs n/a

CasePA006 2yo report, Taiwan

CasePresentingHPOs HP:0011343, HP:0003571

(moderate global developmental delay, propionicacidemia)

HPOsFreeText did not experience other classical PA phenotype after liver transplant(10mo) during 12-month follow up. Urine methylcitrate levels and serum propionylcarnitine levels have not markedly decreased

CaseNotHPOs n/a

CasePreviousTesting coding regions and flanking areas of PCCA also analyzed with PCR and Sanger

Variant 1. NM_000532.4(PCCB):c.1301C>T (p.Ala434Val), 2. NM_000532.4(PCCB):c.1534C>T (p.Arg512Cys)

ClinVar 1. 554490, 2. 38879

gnomAD 1. MAF=0.0003510(East Asian), no homozygotes, 2. MAF=0.00005440(East Asian), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

CasePA005-2 8yo report, Taiwan

CasePresentingHPOs HP:0003571, HP:0011968, HP:0002013, HP:0001987, HP:0011343

(propionicacidemia, poor feeding, vomiting, hyperammonemia, moderate developmental delay)

CaseNotHPOs n/a

CasePreviousTesting coding regions and flanking areas of PCCA also analyzed with PCR and Sanger

Variant 1. NM_000532.4(PCCB):c.1301C>T (p.Ala434Val), 2. NM_000532.4:c.-4156_183+3713del

ClinVar 1. 554490, 2. n/a

CAID 2. n/a

gnomAD 1. MAF=0.0003510(East Asian), no homozygotes, 2. n/a

CaseAddInfo Older sister presented at two weeks old with poor feeding, vomiting, hyperammonemia, metabolic acidosis, recurrent infection, and elevated urine 3-hydroxypropionic and 2-methyl-3-hydroxybutyric acids suggestive of PA. Died of severe infection at 1yr 6mo without genetic testing

CasePMIDs n/a

CasePA004 40do onset, Taiwan

CasePresentingHPOs HP:0003571, HP:0001987, HP:0011968, HP:0001263, HP:0000952, HP:0001942, HP:0001522

(propionicacidemia, hyperammonemia, poor feeding, developmental delay, jaundice, metabolic acidosis, death in infancy)

HPOsFreeText severe jaundice and other symptoms at 40days old. Death at 1yr 6mo

CaseNotHPOs n/a

CasePreviousTesting coding regions and flanking areas of PCCA also analyzed with PCR and Sanger

Variant NM_000532.4(PCCB):c.1301C>T (p.Ala434Val), homozygous

ClinVar 554490

gnomAD MAF= 0.0003510(East Asian), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

CasePA003 3do onset, Taiwan

CasePresentingHPOs HP:0003571, HP:0000952, HP:0011968, HP:0001290, HP:0001942, HP:0002154, HP:0001987, HP:0001522

(propionicacidemia, jaundice, poor feeding, hypotonia, metabolic acidosis, hyperglycinemia, hyperammonemia, death in infancy)

HPOsFreeText died at 5m 15days (also check 2178070 first)

CaseNotHPOs "

NotHPOsFreeText "

CasePreviousTesting coding regions and flanking areas of PCCA also analyzed with PCR and Sanger + "

Variant 1. NM_000532.4(PCCB):c.1301C>T (p.Ala434Val), 2. NM_000532.4:c.580T>C (p.Ser194Pro)

ClinVar 1. 554490, 2. n/a

CAID 2. CA354641839

gnomAD 1. MAF=0.0003510(East Asian), no homozygotes, 2. not in gnomAD

CaseAddInfo "

CasePMIDs 2178070

CasePA002-2 prenatal diagnosis, Taiwan

CasePresentingHPOs HP:0003571

(propionicacidemia)

CaseNotHPOs n/a

CasePreviousTesting coding regions and flanking areas of PCCA also analyzed with PCR and Sanger

Variant 1. NM_000532.4(PCCB):c.1316A>G (p.Tyr439Cys), 2. NM_000532.4:c.-4156_183+3713del

ClinVar 1. 225429, 2. n/a

CAID 2. n/a

gnomAD 1. MAF=0.0001631(South Asian), no homozygotes, 2. n/a

CaseAddInfo aborted after prenatal diagnosis. Older sibling presented with recurrent vomiting, conscious disturbance, hyperventilation, metabolic acidosis, and elevated urine 3-hydroxypropionate, 3-hydroxybutyrate, and 3-hydroxyvalerate suggestive of PA. Died at 2yr 8mo without genetic testing.

CasePMIDs n/a

Thinking this needs to be written differently to get into Allele registry, don't know where to start.

"position is located before the beginning of the transcript" error in Allele registry

Is this a variant that only ClinVar would be able to register at this time?