Table 2. Genotype and in vitro MTHFR activity characteristics in 33 patients with severe MTHFR deficiency (adapted from Burda et al 2015).
| Patients with very low in vitro enzyme activity (<1.5%) | ||||||||
|---|---|---|---|---|---|---|---|---|
| ID | Age at presentation (months) | Mutation allele 1 | Predicted amino acid change | exon / intron | Mutation allele 2 | Predicted amino acid change | Residual in vitro enzyme activity + aFADa | exon / intron |
| 20 | 0.25 | c.188G>C | p.Trp59Ser | exon 1 | c.188G>C | p.Trp59Ser | < 1.5% | exon 1 |
| 82 | 0.2 | c.349G>A | p.Ala113Thr | exon 2 | c.792+1G>T | splice site | < 1.5% | Intron 4 |
| 39 | 0.75 | c.391C>T | p.His127Tyr | exon 2 | c.655_657del | p.Lys215del | < 1.5% | exon 4 |
| 36 | 2 | c.452A>C | p.Gln147Pro | exon 2 | c.452A>C | p.Gln147Pro | < 1.5% | exon 2 |
| 41 | 4 | c.452A>C | p.Gln147Pro | exon 2 | c.452A>C | p.Gln147Pro | < 1.5% | exon 2 |
| 60 | 1 | c.458_459delinsTT | p.Gly149Val | exon 2 | c.458_459delinsTT | p.Gly149Val | < 1.5% | exon 2 |
| 42 | 0.1 | c.559C>T | p.Arg183* | exon 3 | c.559C>T | p.Arg183* | < 1.5% | exon 3 |
| 44 | 0.5 | c.779T>A | p.Ile256Asn | exon 4 | c.1025T>C | p.Met338Thr | < 1.5% | exon 5 |
| 40 | 0.5 | c.1027T>G | p.Trp339Gly | exon 5 | c.1027T>G | p.Trp339Gly | < 1.5% | exon 5 |
| 48 | 6 | c.1027T>G | p.Trp339Gly | exon 5 | c.1027T>G | p.Trp339Gly | < 1.5% | exon 5 |
| 21 | 1 | c.1179-2delA | p.Trp389Trpfs*1 | intron 6 | c.1179-2delA | p.Trp389Trpfs*1 | < 1.5% | intron 6 |
| 25 | - | c.1420G>T | p.Glu470* | exon 8 | c.1420G>T | p.Glu470* | < 1.5% | exon 8 |
| 22 | 2.5 | c.1542G>A | (p.Lys510=)/splicing | exon 8 | c.1542G>A | (p.Lys510=)/splicing | < 1.5% | exon 8 |
| 51 | 1 | c.1542G>A | (p.Lys510=)/splicing | exon 8 | c.1542G>A | (p.Lys510=)/splicing | < 1.5% | exon 8 |
| Patients with in vitro enzyme activity >1.5% | ||||||||
| Cell lines with in vitro FAD responsiveness | ||||||||
| 32 | 3.4 | c.482G>A | p.Arg157Gln | exon 2 | c.482G>A | p.Arg157Gln | 10.4% | exon 2 |
| 55 | 0.3 | c.535G>A | p.Ala175Thr | exon 3 | c.1178G>A | (p.Trp389*) /splicing | 1.7% | exon 6 |
| 33 | 216 | c.596C>T | p.Ala195Val | exon 3 | c.596C>T | p.Ala195Val | 17% | exon 3 |
| Cell lines with reduced affinity for bNADPHbNADPH | ||||||||
| 30 | 132 | c.-40_-41delTC | - | 5’ UTR | c.1727C>T | p.Pro572Leu | 9.9% | exon 10 |
| 29 | 2 | c.276_314dup | p.Leu89_Pro101dup | exon 2 | c.1528T>G | p.Tyr506Asp | 8.1% | exon 8 |
| 52 | 0.1 | c.1126A>G | p.Lys372Glu | exon 6 | c.1542+2T>C | p.Tyr512Trpfs*3 | 6.3% | exon 8 |
| 54 | 0.75 | c.1141C>T | p.Arg377Cys | exon 6 | c.1359+1G>A | splice site | 7.4% | intron 7 |
| 31 | 60 | c.1142G>A | p.Arg377His | exon 6 | c.1142G>A | p.Arg377His | 34.8% | exon 6 |
| 10 | - | c.1274G>C | p.Trp421Ser | exon 7 | c.1420G>T | p.Glu470* | 3.8% | exon 8 |
| 37 | 2.5 | c.1644+2T>G | splice site | intron 9 | c.1644+2T>G | splice site | 1.8% | intron 9 |
| 12 | 1.25 | c.1764+1G>T | splice site | intron 10 | c.1764+1G>T | splice site | 3.7% | intron 10 |
| 14 | - | c.1764+1G>T | splice site | intron 10 | c.1764+1G>T | splice site | 3.0% | intron 10 |
| 13 | 1.25 | c.1765-18G>A | p.Asp585Glyfs*14 | intron 10 | c.1765-18G>A | p.Asp585Glyfs*14 | 2.5% | intron 10 |
| 26 | 24 | c.1765-18G>A | p.Asp585Glyfs*14 | intron 10 | c.1765-18G>A | p.Asp585Glyfs*14 | 3.5% | intron 10 |
| 49 | 1 | c.1780delC | p.Leu590Cysfs*72 | exon 11 | c.1780delC | p.Leu590Cysfs*72 | 2.0% | exon 11 |
| 38 | 1 | c.1805T>C | p.Leu598Pro | exon 11 | c.1805T>C | p.Leu598Pro | 3.1% | exon 11 |
| Cell lines with normal affinity for bNADPHb | ||||||||
| 4 | 156 | c.148C>T | p.Arg46Trp | exon 1 | c.167G>A | p.Arg52Gln | 9.7% | exon 1 |
| 35 | 6 | c.148C>T | p.Arg46Trp | exon 1 | c.1982G>C | p.*657Serext*50 | 2.3% | exon 11 |
| 72 | 4 | c.1332G>C | p.Ser440=/splicing | exon 7 | c.1644+2T>G | splice site | 2.2% | intron 9 |
a
FAD flavin adenine dinucleotide
b
Nicotinamide adenine dinucleotide phosphate