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Table 1 Genetic and biochemical findings of validation and discovery cases

From: Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants

Reference Gene Allele 1 Nucleotide change (protein effect) HGMD number Allele 2 Nucleotide change (protein effect) HGMD number Clinical and biochemical findings
VC1 TCN2 a c.497_498delTC (p.Leu166Profs*7) CD106933 c.497_498delTC (p.Leu166Profs*7) CD106933 2 m pancytopenia, FTT, metabolic acidosis. Improvement after im OHCbl
↑Hcys (pl): 26 μmol/L; ↑C3: 3.4 μmol/L; ↑MMA (ur): 419 mmol/mol creatn
Propionate uptake (FB) (nmol/10 h/mg prot): Normal
-OHCbl (patient/control): 0.76/0.97
+OHCbl (patient/control): 0.98/0.83
VC2 MTR a c.1348_1349delTCinsGA (p.Ser450Asp) c.3008-4A > G (p.?) CS135282 2 m apnea, somnolence, hypotonia, seizures
↑Hcys (pl): 79 μmol/L; MMA (ur) (N)
VC3 MTRR c.1361C > T (p.Ser454Leu) CM032288 c.1769 + 1G > A (p.Glu560_Arg590del) MGA, low serum vit B12; ↑Hcys (pl): 90 μmol/L; N MMA (ur)
VC4 MMACHC c.271dupA (p.Arg91Lysfs*14) CI055013 c.271dupA (p.Arg91Lysfs*14) CI055013 NBS: ↑C3 + C3/C2 in DBS
↑Hcys (pl); ↑MMA (ur) > 1000 mmol/mol creatn
VC5 MMACHC a c.271dupA (p.Arg91Lysfs*14) CI055013 c.626dupT (p.Thr210Aspfs*35) CI095519 NBS: ↑C3 in DBS
↑Hcys: 159 μmol/L; C3 (pl): 8.2 μmol/L; ↑MMA (ur): 608 mmol/mol creatn
Propionate uptake (FB) (nmol/10 h/mg prot):
-OHCbl (patient/control): 0.23/1.90
+OHCbl (patient/control): 2.3/2.34
VC6 MMADHC a c.57_64del8 (p.Ser20*) CD082071 c.57_64del8 (p.Ser20*) CD082071 4d hypotonia, metabolic acidosis, hyperammonemia
N Hcys (pl); ↑MMA (ur): 5875 mmol/mol creatn;
Propionate uptake (FB) (nmol/10 h/mg prot):
-OHCbl (patient/control): 0.13/3.31
+OHCbl (patient/control): 2.30/3.37
Mutase (FB):N
VC7 MUT a c.312delC (p.Trp105Glyfs*75) c.1846C > T (p.Arg616Cys) CM050688 12 m metabolic acidosis
↑MMA (ur): 8810 mmol/mol creatn
VC8 MMAA a c.64C > T (p.Arg22Ter) CM042745 c.433C > T (p.Arg145Ter) CM042746 5 m metabolic acidosis. Improvement after im OHCbl
↑MMA (ur)
Propionate uptake (FB) (nmol/10 h/mg prot):
-OHCbl (patient/control): 0.12/1.32
+OHCbl (patient/control): 0.42/2.17
Mutase (FB): N
VC9 MMAB a c.548A > T (p.His183Leu) CM154654 c.570_572dupCCG (p.Arg191dup) CI154655 NBS: ↑C3 in DBS
↑C3 (pl): 7.7 μmol/L; ↑MMA (ur): 830 mmol/mol creatn
Propionate uptake (FB) (nmol/10 h/mg prot):
-OHCbl (patient/control): 0.63/1.90
+OHCbl (patient/control): 1.19/2.34
Mutase (FB): N
P1 TCN1 c.901G > Tb (p.Asp301Tyr) CM099555 c.901G > Tb (p.Asp301Tyr) CM099555 Adult with neurological symptoms and low serum vit B12. Improvement after im OHCbl
↑N Hcys (pl): 17 μmol/L
P2 TCN1 c.901G > Tb (p.Asp301Tyr) CM099555 c.901G > Tb (p.Asp301Tyr) CM099555 Adult with slight anemia and low serum vit B12.
Improvement after im OHCbl
P3 GIF a c.389C > G (p.Ser130Ter) c.389C > G (p.Ser130Ter) 7y, anemia since 15 m; low serum vit B12. Improvement after im OHCbl
↑Hcys (pl): 49 μmol/L
P4 AMN a c.514-34G > A (p.Thr172fs) CS127867 c.1046C > A (p.Ser349Ter) 2y, megaloblastic anemia with low serum vit B12. Improvement after im OHCbl
↑Hcys (pl): 39.9 μmol/L
P5 MMAA c.593_596delCTGA (p.Thr198Serfs*6) CD043681 c.593_596delCTGA (p.Thr198Serfs*6) CD043681 ↑MMA (ur)
P6 MUT a c.904G > C (p.Ala302Pro) c.904G > C (p.Ala302Pro) NBS: ↑C3 + C3/C2 in DBS
↑MMA (ur): > 1000 mol/mol creatn
Propionate uptake (FB) (nmol/10 h/mg prot) - > (mut0)
-OHCbl (patient/control): 0.18/1.16
+OHCbl (patient/control): 0.11/1.02
P7 MUT a c.671_678dupAATTTATG (p.Val227Asnfs*16) CI050942 c.607G > A (p.Gly203Arg) CM002067 Neonatal presentation
↑MMA (ur)
P8 MUT c.313 T > C (p.Trp105Arg) CM900166 c.2150G > T (p.Gly717Val) CM920488 7 m metabolic acidosis, lethargy
↑MMA (ur)
P9 MUT a c.2026G > A (p.Ala676Thr) c.2026G > A (p.Ala676Thr) NBS: ↑C3/C2 in DBS
↑C3 (pl): 2.4 μmol/L; ↑MMA (ur): 772 mmol/mol creatn
Propionate uptake (FB) (nmol/10 h/mg prot) - > (mut-)
-OHCbl (patient/control): 0.25/1.16
+OHCbl (patient/control): 1.16/1.02
P10 MUT a c.243dupA (p.Pro82Thrfs*2) c.1084-10A > G (p.?) CS128372 ↑MMA (ur)
P11 MUT a
TCN1a
c.454C > T (p.Arg152Ter) CM050671 c.901G > Tb (p.Asp301Tyr) CM099555 ? NBS: ↑C3 in DBS
Low serum vit B12; ↑N MMA (ur): 17–58 mmol/mol creatn
P12 MUT c.671_678dupAATTTATG (p.Val227Asnfs*16) CI050942 c.671_678dupAATTTATG (p.Val227Asnfs*16) CI050942 Neonatal presentation and fatal outcome
↑MMA (ur)
P13 MUT a c.1420C > T (p. Arg474Ter) CM050685 c.2026G > A (p.Ala676Thr) NBS: ↑C3/C2 in DBS
↑C3 (pl): 3.4 μmol/L; ↑MMA (ur): 276 mmol/mol creatn
Propionate uptake (FB) (nmol/10 h/mg prot) - > (mut-)
-OHCbl (patient/control): 0.28/1.33
+OHCbl (patient/control): 1.13/1.57
P14 MMAB a c.220G > T (p.Glu74Ter) c.548A > T (p.His183Leu) CM154654 NBS: ↑C3/C2 in DBS
↑C3 (pl): 3.64 μmol/L; ↑MMA (ur): 68 mmol/mol creatn
P15 CD320 a c.262_264delGAG (p.Glu88del) CD104789 c.142 + 5G > A (p.?) NBS: ↑C3 + C3/C2 in DBS
↑Hcys (pl): 18.3 μmol/L; N C3 + C4DC (pl); ↑MMA (ur): 25–170 mmol/mol creatn
P16 MMACHC a c.347 T > C (p.Leu116Pro) CM060067 c.347 T > C (p.Leu116Pro) CM060067 NBS: ↑C3 + C3/C2 in DBS
↑MMA (ur): 2000 mmol/mol creatn
P17 MMACHC a c.271dupA (p.Arg91Lysfs*14) CI055013 c.271dupA (p.Arg91Lysfs*14) CI055013 4d: hypotonia, weight loss, vomiting, ↑lac
↑Hcys (pl): 214 μmol/L; ↑C3: 6.5 μmol/L + ↑C4DC (pl): 0.25 μmol/L
↑MMA (ur): 1197 mmol/mol creatn
P18 MMACHC c.271dupA (p.Arg91Lysfs*14) CI055013 c.271dupA (p.Arg91Lysfs*14) CI055013 ↑Hcys (pl); ↑MMA (ur)
P19 MMADHC a c.748C > T (p.Arg250Ter) CM081188 c.748C > T (p.Arg250Ter) CM081188 NBS: ↑C3 + C3/C2 in DBS
↑Hcys (pl): 51 μmol/L; ↑C3 (pl): 4.8 μmol/L; MMA (ur): 290 mmol/mol creatn
P20 MMADHC a c.748C > T (p.Arg250Ter) CM081188 c.748C > T (p.Arg250Ter) CM081188 NBS: ↑C3 + C3/C2 in DBS
↑Hcys (pl): 59 μmol/L; ↑C3 (pl): 8.5 μmol/L; MMA (ur): 1175 mmol/mol creatn
P21 MTRR c.1361C > T (p.Ser454Leu) CM032288 c.1361C > T (p. Ser454Leu) CM032288 17 m; anemia, psychomotor delay
↑Hcys (pl): 76 μmol/L
P22 MTRR c.1361C > T (p.Ser454Leu) CM032288 c.1678_1681delGAGA (p.Glu560Asnfs*42) CD159487 10 m seizures, megaloblastic anemia
↑Hcys (pl): 89 μmol/L
P23 SUCLA2 a c.976G > C (p.Gly326Arg) c.935 T > C (p.Ile312Thr) Hypoglycemia at birth, slight PMD during first years
Asymptomatic at 11y
↑-N C3(pl): 1–2.2 μmol/L + C4DC
↑N Lac, 3-OHProp, MMA 27 mmol/mol creatn, MC (ur)
Normal carboxylases activities (FB)
Propionate uptake (FB) (nmol/10 h/mg prot) - > Normal
-OHCbl (patient/control): 0.71/0.75
+OHCbl (patient/control): 0.79/1.13
P24 ACSF3 a c.424C > T (p.Gln142Ter) c.1446_1447delCA (p.Tyr482Ter) NBS: ↑MMA (ur) since newborn: 512 mmol/mol creatn
Asymptomatic at 3y
P25 ACSF3 a c.1075G > A (p.Glu359Lys) CM116777 c.1075G > A (p.Glu359Lys) CM116777 5y PMD, bilateral sensorineural hearing loss
AC (pl): N; ↑MMA (ur): 360 mmol/mol creatn
P26 ACSF3 a c.1075G > A (p.Glu359Lys) CM116777 c.1672C > T (p.Arg558Trp) CM116840 Seizures since first months of age
At 12y seizures + dystonia
AC (pl): N; ↑MMA (ur): 124–560 mmol/mol creatn
Normal propionate uptake ± OHCbl (FB)
P27 ACSF3 c.820C > T (p.Gln274Ter) c.820C > T (p.Gln274Ter) NBS: ↑MMA (ur) since newborn. Asymptomatic at 7 m
  1. VC validation case, C3 propionylcarnitine, C2 acetylcarnitine, C4DC methylmalonylcarnitine, DBS dried blood spots, FB fibroblasts, Hcys homocysteine, im intramuscular, MMA methylmalonic acid, OHCbl hydroxocobalamin, ur urine, pl plasma, Lac Lactate, MC methylcitrate, NBS newborn screening, PMD psychomotor delay
  2. aMutations confirmed in parents; b Variant with uncertain clinical significance; new mutations in bold
  3. Mutations named according to GenBank accession number included in Additional file 3: Table S1