Number | Exon/Intron | Nucleotide alteration | Protein alteration | Mutation type | Early/late onset | ACMG classification | CADD scores | MSC scores | References | Clinical features | Treatment | Outcome |
---|---|---|---|---|---|---|---|---|---|---|---|---|
PCCA | ||||||||||||
1 | Exon10 | NM_000282.4:c.802C > T | p.Arg268Cys | Missense | Late | Pathogenic | 22.5 | 20 | [110] | No specific clinical symptoms | NA | Following up eleven times within one year and three months after birth, liver and kidney function were normal |
 | Exon11 | NM_000282.4:c.827delG | p.Gly276Valfs*46 | Frameshift | Likely Pathogenic | NA | NA | |||||
2 | Intron8 | NM_000282.4:c.638-1G > C | NA | Splice site mutation | Early | Likely Pathogenic | 33 | 20 | [61] | Mild anemia or mild jaundice, hyperammonemia, hyperlactatemia and hypoglycemia | Protein restriction with special protein powder and sufficient calories, L-carnitine and arginine supplementation, and regular follow-up checks | Normal development and no acute metabolic disorders were observed during the course of management |
 | NA | NA | NA | NA | NA | NA | NA | |||||
3 | Exon9 | NM_000282.4:c.688C > T | p.Arg230Cys | Missense | Pathogenic | 28.3 | 20 | |||||
 | Intron13 | NM_000282.4:c.1209 + 2 T > G | NA | Splice donor | Pathogenic | 34 | 20 | |||||
4 | Intron2 | NM_000282.4:c.183 + 1G > C | NA | Splice site mutation | Likely Pathogenic | 33 | 20 | |||||
 | Exon21 | NM_000282.4:c.1850 T > C | p.Leu617Pro | Missense | Likely Benign | 24.5 | 20 | |||||
5 | Exon22 | NM_000282.4:c.2002G > A | p.Gly668Arg | Missense | Pathogenic | 32 | 20 | Development delay in early infancy | ||||
 | Exon22 | NM_000282.4:c.2040G > A | p.Ala680Ala | Synonymous | Likely Pathogenic | 24 | 20 | |||||
6 | Exon22 | NM_000282.4:c.2002G > A | p.Gly668Arg | Missense | Pathogenic | 32 | 20 | |||||
 | Exon2 | NM_000282.4:c.131delinsATT | p.Cys44Tyrfs*3 | Missense | Pathogenic | NA | NA | |||||
7 | Intron3 | NM_000282.4:c.231 + 1G > A | NA | Splice site mutation | Likely Pathogenic | 34 | 20 | NA | ||||
 | Exon7 | NM_000282.4:c.596 T > A | p.Val199Asp | Missense | Uncertain Significance | 28.1 | 20 | |||||
8 | Exon22 | NM_000282.4:c.2002G > A | p.Gly668Arg | Missense | Early | Pathogenic | 32 | 20 | [59] | Respiratory failure, granulocytopenia, and cardiac damage with rapid progression | Anti-infection measures, atomization therapy, sputum suction, glucose infusion, protein restriction, and supplementation with calcium, arginine, l-carnitine, and l-creatinine phosphate. Efforts were also made to strengthen the respiratory tract and correct acidosis | Died at the age of eighth day after birth |
 | Exon22 | NM_000282.4:c.2002G > A | p.Gly668Arg | Missense | Pathogenic | 32 | 20 | |||||
9 | Exon22 | NM_000282.4:c.2002G > A | p.Gly668Arg | Missense | Pathogenic | 32 | 20 | Disorders of consciousness, poor feeding, hyperammonemia, and metabolic acidosis | Anti-infection, fasting, restriction of protein intake, supplementation of hypertonic glucose, arginine iv to promote ammonia excretion | Died at the age of one month and seven days after birth | ||
 | Exon22 | NM_000282.4:c.2002G > A | p.Gly668Arg | Missense | Pathogenic | 32 | 20 | |||||
10 | Intron20 | NM_000282.4:c.1845 + 1G > A | NA | Splice site mutation | Early | Pathogenic | 34 | 20 | [111] | NA | NA | Died during the neonatal period |
 | Exon6 | NM_000282.4:c.446del | p.Asn149Thrfs*35 | Frameshift | Pathogenic | NA | NA | |||||
11 | Intron20 | NM_000282.4:c.1845 + 1G > A | NA | Splice site mutation | NA | Pathogenic | 34 | 20 | Coma, convulsions, bronchopneumonia, anemia, thrombocytopenia | NA | Died after more than seven months old | |
 | Exon6 | NM_000282.4:c.446del | p.Asn149Thrfs*35 | Frameshift | Pathogenic | NA | NA | |||||
12 | Exon3 | NM_000282.4:c.229C > T | p.Arg77Trp | Missense | NA | Pathogenic | 25.1 | 20 | [112] | NA | NA | NA |
 | Intron21 | NM_000282.4:c.1899 + 1G > A | NA | Splice site mutation | Likely Pathogenic | NA | NA | |||||
13 | Exon14 | NM_000282.4:c.1262A > C | p.Gln421Pro | Missense | Newborn screening | Uncertain Significance | 22.8 | 20 | [64] | No typical PA symptoms, no hyperammonemia | Low-protein diet and l-carnitine supplementation | No significant development delay |
 | Exon3 | NM_000282.4:c.229C > T | p.Arg77Trp | Missense | Pathogenic | 25.1 | 20 | |||||
14 | Exon15 | NM_000282.4:c.1288C > T | p.Arg430Ter | Nonsense | Newborn screening | Pathogenic | 37 | 20 | [113] | NA | NA | NA |
 | Exon3 | NM_000282.4:c.229C > T | p.Arg77Trp | Missense | Pathogenic | 25.1 | 20 | |||||
15 | Intron13 | NM_000282.4:c.1210-7C > G | NA | Splice site mutation | Newborn screening | Uncertain Significance | 25.3 | 20 | NA | NA | NA | |
 | Exon13 | NM_000282.4:c.1185A > C | p.Ala395Ala | Samesense | Likely Benign | 9.037 | 20 | |||||
16 | Exon22 | NM_000282.4:c.2002G > A | p.Gly668Arg | Missense | Newborn screening | Pathogenic | 32 | 20 | [114] | NA | NA | NA |
 | Exon22 | NM_000282.4:c.2002G > A | p.Gly668Arg | Missense | Pathogenic | 32 | 20 | |||||
17 | Exon12 | NM_000282.4:c.937C > T | p.Arg313Ter | Nonsense | Early | Pathogenic | 38 | 20 | [37] | Tachypnea, poor reaction, seizures, lethargy, irritability | Antibiotics treatment, supplementation of l-carnitine, folic acid, and biotin; protein restriction | Died at approximately two months of age |
 | Exon10- | NM_000282.4:c.773_819 + 47delinsAA | NA | Complex deletion– | Likely Pathogenic | NA | NA | |||||
Intron10 | Insertion (delins) mutation | |||||||||||
18 | Exon15 | NM_000282.4:c.1288C > T | p.Arg430Ter | Nonsense | Early | Pathogenic | 37 | 20 | [7] | Generalized tonic–clonic seizures, metabolic acidosis and hyperammonemia | NA | Died at six and a half months old from sudden cardiac arrest |
 | Exon22 | NM_000282.4:c.2002G > A | p.Gly668Arg | Missense | Pathogenic | 32 | 20 | |||||
19 | Exon16 | NM_000282.4:c.1426C > T | p.Arg476Ter | Nonsense | Early | Pathogenic | 41 | 20 | Recurrent vomiting, lethargy and dyspnea | Low-isoleucine, − methionine, − threonine, and-valine diet, supplementation of l-carnitine and biotin | Mild intellectual disability | |
 | Exon16 | NM_000282.4:c.1426C > T | p.Arg476Ter | Nonsense | Pathogenic | 41 | 20 | |||||
20 | Exon19 | NM_000282.4:c.1746G > C | P.Ser582Ser | Synonymous | Early | Uncertain Significance | 9.081 | 20 | [36] | Cough, tachypnea, dyspnea and metabolic acidosis | NA | Died due to respiratory failure |
 | Exon3-4 | NM_000282.4:Exon3-4del | NA | NA | NA | NA | NA | |||||
21 | Exon19 | NM_000282.4:c.1746G > C | P.Ser582Ser | Synonymous | Early | Uncertain Significance | 9.081 | 20 | Cough, tachypnea, dyspnea and metabolic acidosis | NA | NA | |
 | Exon3-4 | NM_000282.4:Exon3-4del | NA | NA | NA | NA | NA | |||||
22 | Exon22 | NM_000282.4:c.2002G > A | p.Gly668Arg | Missense | Late | Pathogenic | 32 | 20 | [62] | Poor feeding, intermittent vomiting, dilated cardiomyopathy | Liver transplantation | Liver transplantation improved cardiac function but did not significantly impact growth, even with a normal diet, except when supplemented with l-carnitine |
 | Exon22 | NM_000282.4:c.2002G > A | p.Gly668Arg | Missense | Pathogenic | 32 | 20 | |||||
23 | Exon21 | NM_000282.4:c.1850 T > C | p.Leu617Pro | Missense | Newborn screening | Likely Benign | 24.5 | 20 | [108] | NA | NA | NA |
 | Exon4 | NM_000282.4:c.297 T > A | p.Ser99Arg | Missense | Uncertain Significance | 20.4 | 20 | |||||
24 | Intron15 | NM_000282.4:c.1353 + 5_1353 + 9del | NA | Splice site mutation | Late | Uncertain Significance | NA | NA | [52] | NA | Low protein diet, special milk powder, oral l-carnitine and arginine | Physical and intellectual development is normal and noacute metabolic disorders |
 | NA | NA | NA | NA | NA | NA | NA | |||||
25 | Exon3 | NM_000282.4:c.229C > T | p.Arg77Trp | Missense | Newborn screening | Pathogenic | 25.1 | 20 | [109] | NA | NA | NA |
 | Exon22 | NM_000282.4:c.2002G > A | p.Gly668Arg | Missense | Pathogenic | 32 | 20 | |||||
PCCB | ||||||||||||
1 | Exon13 | NM_000532.5:c.1301C > T | p.Ala434Val | Missense | Early | Pathogenic | 32 | 20 | [65] | Poor feeding, hyperglycinemia, hyperammonemia, metabolic acidosis, early recurrent infections, and development delay | Sodium bicarbonate IV to correct acidosis, l-carnitine supplementation, BCAA restriction and protein intake reduction | Obvious development delay and intellectual disability |
 | Exon13 | NM_000532.5:c.1301C > T | p.Ala434Val | Missense | Pathogenic | 32 | 20 | |||||
2 | Exon1 | NM_000532.5:c.167_179del13insC | p.Asp56_Lys60delinsAla | Deletion and insertion mutation | Late | NA | NA | NA | Hyperglycininemia | l-carnitine supplementation, BCAA restriction and protein intake reduction | Mental and language development is slightly delayed | |
 | Exon1 | NM_000532.5:c.167_179del13insC | p.Asp56_Lys60delinsAla | Deletion and insertion mutation | NA | NA | NA | |||||
3 | Exon1 | NM_000532.5:c.132_134delGACinsAT | p.Thr45SerfsTer20 | Deletion and insertion mutation | Early | Likely Pathogenic | NA | NA | [115] | Repeated seizures, hyperammonemia, ketoacidosis, hyperglycaemia, anemia | Protein restriction along with phenobarbital, l-carnitine, and arginine supplementation. Treatments to correct acidosis and electrolyte disorders | Symptoms were improved |
 | NA | NA | NA | NA | NA | NA | NA | |||||
4 | Exon14 | NM_000532.5:c.1403C > T | p.Ala468Val | Missense | Early | Likely Pathogenic | 27.1 | 20 | [61] | Mild anemia or mild jaundice, metabolic acidosis, hyperammonemia, hyperlactatemia and hypoglycemia | Similar to PCCA cases No. 2- 7 | Physical and intellectual development is normal |
 | Exon8 | NM_000532.5:c.838dup | p.Leu280fs | Frameshift | Pathogenic | NA | NA | |||||
5 | Intron1 | NM_000532.5:c.184-2A > G | NA | Splice site mutation | Early | Pathogenic | 33 | 20 | Repeated vomiting, lethargy, dyspnea, hypotonia, metabolic acidosis, hyperammonemia, liver dysfunction | Death from an acute metabolic disorder occurred at the age of seven months | ||
 | Exon7 | NM_000532.5:c.733G > A | p.Gly245Ser | Missense | Likely Pathogenic | 28.9 | 20 | |||||
6 | Exon3 | NM_000532.5:c.331C > T | p.Arg111Ter | Nonsense | Early | Pathogenic | 36 | 20 | [116] | Lethargy, poor feeding | l-carnitine, special milk powder | Died at three months old after birth |
 | Exon12 | NM_000532.5:c.1228C > T | p.Arg410Trp | Missense | Pathogenic | 37 | 20 | |||||
7 | Exon1 | NM_000532.5:c.146delG | p.Gly49Glufs*16 | Frameshift | Late | Likely Pathogenic | NA | NA | Vomiting, lethargy, poor spirit | l-carnitine, special milk powder | Poor compliance and intermittent treatment, significant development delay | |
 | Exon12 | NM_000532.5:c.1253C > T | p.Ala418Val | Missense | Likely Pathogenic | 27.4 | 20 | |||||
8 | Exon10 | NM_000532.5:c.1087 T > C | p.Ser363Pro | Missense | Late | Likely Pathogenic | 30 | 20 | [47] | NA | NA | NA |
 | Exon10 | NM_000532.5:c.1087 T > C | p.Ser363Pro | Missense | Likely Pathogenic | 30 | 20 | |||||
9 | Intron1 | NM_000532.5:c.184-2A > G | NA | Splice site mutation | Early | Pathogenic | 33 | 20 | [117] | Abdominal distension, vomiting, poor feeding, dyspnea, and hyperammonemia | NA | NA |
 | Exon7 | NM_000532.5:c.733G > A | p.Gly245Ser | Missense | Likely Pathogenic | 28.9 | 20 | |||||
10 | NA | NA | NA | NA | Late | NA | NA | NA | [64] | Recurrent vomiting, disorders of consciousness, hyperventilation, and metabolic acidosis | NA | Died at the age of two years and eight months after birth |
 | NA | NA | NA | NA | NA | NA | NA | |||||
11 | Exon13 | NM_000532.5:c.1316A > G | p.Tyr439Cys | Missense | Prenatal diagnosis | Pathogenic | 31 | 20 | NA | NA | Miscarriage occurred at twenty-one weeks of gestation | |
 | Intron1 | NM_000532.5:c.-4156_183 + 3713del | NA | NA | NA | NA | NA | |||||
12 | Exon13 | NM_000532.5:c.1301C > T | p.Ala434Val | Missense | Early | Pathogenic | 32 | 20 | Jaundice, poor feeding, hypotonia, metabolic acidosis, hyperglycaemia, and hyperammonemia | NA | NA | |
 | Exon5 | NM_000532.5:c.580 T > C | p.Ser194Pro | Missense | Likely Pathogenic | 28.8 | 20 | |||||
13 | Exon13 | NM_000532.5:c.1301C > T | p.Ala434Val | Missense | Early | Pathogenic | 32 | 20 | Poor feeding, severe jaundice, metabolic acidosis, and hyperammonemia | NA | Died at the age of one year and eight months after birth | |
 | Exon13 | NM_000532.5:c.1301C > T | p.Ala434Val | Missense | Pathogenic | 32 | 20 | |||||
14 | NA | NA | NA | NA | Early | NA | NA | NA | Poor feeding, vomiting, hyperammonemia, metabolic acidosis, and recurrent infections | NA | Died at the age of one year and six months of a severe infection | |
 | NA | NA | NA | NA | NA | NA | NA | |||||
15 | Intron1 | NM_000532.5:c.-4156_183 + 3713del | NA | NA | Prenatal diagnosis | NA | NA | NA | Poor feeding, vomiting, and hyperammonemia | l-carnitine, special milk powder, phenylbutyric acids | Moderate developmental delay | |
 | Exon13 | NM_000532.5:c.1301C > T | p.Ala434Val | Missense | Pathogenic | 32 | 20 | |||||
16 | Exon13 | NM_000532.5:c.1301C > T | p.Ala434Val | Missense | Newborn screening | Pathogenic | 32 | 20 | Classic PA phenotype and moderate developmental delay | Low-protein diet supplemented with l-carnitine, metronidazole, and growth hormone, liver transplantation | No classical PA phenotypic symptoms was observed during the twelve-month follow-up after liver transplantation | |
 | Exon15 | NM_000532.5:c.1534C > T | p.Arg512Cys | Missense | Pathogenic | 28.6 | 20 | |||||
17 | Exon13 | NM_000532.5:c.1301C > T | p.Ala434Val | Missense | Early | Pathogenic | 32 | 20 | Hypoactivity, poor feeding and tachypnea hypotonia, hepatomegaly, disorders of consciousness, and hyperammonemia | NA | Died at six days old after birth | |
 | Exon8 | NM_000532.5:c.838dup | p.Leu280fs | Frameshift | Pathogenic | NA | NA | |||||
18 | Intron1 | NM_000532.5:c.-4156_183 + 3713del | NA | NA | Newborn screening | NA | NA | NA | Hyperammonemia and hypoglycemia | Low-protein diet supplemented with l-carnitine | Mild development delay | |
 | Exon13 | NM_000532.5:c.1301C > T | p.Ala434Val | Missense | Pathogenic | 32 | 20 | |||||
19 | Exon8 | NM_000532.5:c.838dup | p.Leu280fs | Frameshift | Newborn screening | Pathogenic | NA | NA | [67] | NA | NA | NA |
 | Exon13 | NM_000532.5:c.1316A > G | p.Tyr439Cys | Missense | Pathogenic | 31 | 20 | |||||
20 | Exon8 | NM_000532.5:c.838dup | p.Leu280fs | Frameshift | Pathogenic | NA | NA | |||||
 | Exon13 | NM_000532.5:c.1316A > G | p.Tyr439Cys | Missense | Pathogenic | 31 | 20 | |||||
21 | Exon3 | NM_000532.5:c.370C > T | p.Gln124Ter | Nonsense | Likely Pathogenic | 48 | 20 | |||||
 | Exon12 | NM_000532.5:c.1283C > T | p.Thr428Ile | Missense | Pathogenic | 27.9 | 20 | |||||
22 | Exon3 | NM_000532.5:c.331C > T | p.Arg111Ter | Nonsense | Pathogenic | 36 | 20 | |||||
 | Exon10 | NM_000532.5:c.1087 T > C | p.Ser363Pro | Missense | Likely Pathogenic | 30 | 20 | |||||
23 | Exon12 | NM_000532.5:c.1220del | p.Gly407Alafs*36 | Frameshift | Pathogenic | NA | NA | |||||
 | Exon10 | NM_000532.5:c.1015A > T | p.Asn339Asp | Missense | Likely Pathogenic | 29.3 | 20 | |||||
24 | Exon13 | NM_000532.5:c.1316A > G | p.Tyr439Cys | Missense | Newborn screening | Pathogenic | 31 | 20 | ||||
 | NA | NA | NA | NA | NA | NA | NA | |||||
25 | Exon8 | NM_000532.5:c.838dup | p.Leu280fs | Frameshift | Early | Pathogenic | NA | NA | [16] | Hypotonia, disorders of consciousness, pancytopenia metabolic acidosis and hyperammonemia | Protein restriction and supplementation of l-carnitine, mannitol, and calories. Correct acidosis and electrolyte disorders | Died from pneumonia approximately thirty days after birth |
 | Exon8 | NM_000532.5:c.838dup | p.Leu280fs | Frameshift | Pathogenic | NA | NA | |||||
26 | Exon6 | NM_000532.5:c.634G > T | p.Asp212Tyr | Missense | Early | Likely Pathogenic | 29.6 | 20 | [118] | Poor feeding, hypotonia, pancytopenia, hyperlactatemia | l-carnitine, vitamin B12, special milk powder, a restricted protein diet | Development delay, intellectual disability |
 | Exon8 | NM_000532.5:c.838dup | p.Leu280fs | Frameshift | Pathogenic | NA | NA | |||||
27 | Exon3 | NM_000532.5:c.359_360delAT | p.Tyr120Cysfs*40 | Frameshift | Early | Likely Pathogenic | NA | NA | [7] | Recurrent infections, diarrhea, metabolic acidosis, and generalized tonic–clonic seizures | Low isoleucine, methionine, threonine and proline diet with the supplementation of l-carnitine and biotin | Moderate intellectual disability and development delay |
 | Intron13 | NM_000532.5:c.1398 + 1G > A | NA | Splice site mutation | Likely Pathogenic | 35 | 20 | |||||
28 | Exon13 | NM_000532.5:C.1381G > C | p.Ala461Pro | Missense | Early | Likely Pathogenic | 30 | 20 | [66] | Vomiting | Special milk powder and oral administration of l-carnitine from 100 to 200 mg/kg every day | NA |
 | Exon13 | NM_000532.5:c.1301C > T | p.Ala434Val | Missense | Pathogenic | 32 | 20 | |||||
29 | Exon13 | NM_000532.5:C.1381G > C | p.Ala461Pro | Missense | Early | Likely Pathogenic | 30 | 20 | Poor feeding | NA | Died due to severe multiple organ failure | |
 | Exon13 | NM_000532.5:c.1301C > T | p.Ala434Val | Missense | Pathogenic | 32 | 20 | |||||
30 | Exon15 | NM_000532.5:c.1535G > A | p.Arg512His | Missense | Early | Pathogenic | 31 | 20 | Poor feeding, lethargy, coma, hypotonia, metabolic acidosis and hyperammonemia | NA | Died from a severe multiple organ failure after the discharge requested by the parents at twenty-four days old | |
 | Exon15 | NM_000532.5:c.1535G > A | p.Arg512His | Missense | Pathogenic | 31 | 20 | |||||
31 | Exon11 | NM_000532.5:c.1131dup | p.Val378Cysfs*5 | Frameshift | Early | Likely Pathogenic | NA | NA | [119] | Lethargy, irregular breathing, with groaning and snoring, hypotonia, non-rosy skin, hypoglycemia, and metabolic acidosis | NA | Died due to respiratory failure |
 | Exon1 | NM_000532.5:c.-10_183 + 10del203 | NA | Deletion mutation | NA | NA | NA | |||||
32 | Exon11 | NM_000532.5:c.1131dup | p.Val378Cysfs*5 | Frameshift | Early | Likely Pathogenic | NA | NA | NA | |||
 | Exon1 | NM_000532.5:c.-10_183 + 10del203 | NA | Deletion mutation | NA | NA | NA | |||||
33 | Exon8 | NM_000532.5:c.838dup | p.Leu280ProfsTer11 | Frameshift | Early | Pathogenic | NA | NA | Poor feeding, hypotonia, sepsisticemia, and multiple organ failure | NA | Died at seven days old after birth | |
 | Exon11 | NM_000532.5:C.1098G > C | P.Leu366Phe | Missense | Likely Pathogenic | 25.8 | 20 | |||||
34 | Intron14 | NM_000532.5:c.1498 + 1G > A | NA | Splice site mutation | Early | Likely Pathogenic | 34 | 20 | NA | NA | Died shortly after birth due to metabolic abnormalities | |
 | Intron14 | NM_000532.5:c.1498 + 1G > A | NA | Splice site mutation | Likely Pathogenic | 34 | 20 | |||||
35 | Exon2 | NM_000532.5:c.224A > C | p.Asp75Ala | Missense | Newborn screening | Likely Pathogenic | 29.9 | 20 | [114] | NA | NA | NA |
 | Exon13 | NM_000532.5:c.1339C > T | p.Leu447Phe | Missense | Uncertain Significance | 25.5 | 20 | |||||
36 | Exon13 | NM_000532.5:c.1301C > T | p.Ala434Val | Missense | Early | Pathogenic | 32 | 20 | [107] | Jaundice, hyperammonemia, and metabolic acidosis | Special milk powder and supplementation of l-carnitine | Regular follow-up revealed mild development delay and intellectual disability |
 | Exon10 | NM_000532.5:c.1087 T > C | p.Ser363Pro | Missense | Likely Pathogenic | 30 | 20 |