Table 1.
All qualified variants in PHGDH in 793 MacTel cases and 17610 controls under a dominant model with gnomAD MAF < 0.001.
| Variant ID Chr-Pos-Ref-Alt |
HGVS.c | HGVS.p | Alleles in 793 MacTel cases | Alleles in 17610 controls | Allele frequency in gnomAD (if available) | REVEL | Polyphen2 HVAR | CADD | Relative enzyme activity to wt protein |
|---|---|---|---|---|---|---|---|---|---|
| 1-120254666-GA-G | c.21_22G | p.Val9Cysfs*32 | 1 | ||||||
| 1-120254667-A-T | c.22A>T | p.Lys8Ter | 1 | 39.0 | |||||
| 1-120263820-G-A | c.166G>A | p.Ala56Thr | 1 | 0.000004 | 0.53 | B | 24.9 | ||
| 1-120263835-G-A | c.181G>A | p.Ala61Thr | 1 | 0.000046 | 0.53 | P | 27.5 | ||
| 1-120263880-G-T | c.226G>T | p.Ala76Ser | 2 | 0.000099 | 0.78 | D | 32.0 | ||
| 1-120263896-A-T | c.242A>T | p.Asp81Val | 1 | 0.000064 | 0.95 | D | 31.0 | ||
| 1-120263899-A-G | c.245A>G | p.Asn82Ser | 2 | 0.000004 | 0.78 | D | 27.0 | ||
| 1-120263904-G-T | c.250G>T | p.Asp84Tyr | 1 | 0.97 | D | 32.0 | |||
| 1-120263941-T-C | c.287T>C | p.Met96Thr | 1 | 0.85 | D | 25.6 | 0.17 | ||
| 1-120266027-G-A | c.319G>A | p.Ala107Thr | 1 | 2 | 0.000078 | 0.89 | D | 34.0 | |
| 1-120266052-T-G | c.344T>G | p.Met115Arg | 1 | 0.78 | B | 25.4 | −0.01 | ||
| 1-120266064-G-C | c.356G>C | p.Arg119Thr | 1 | 0.95 | D | 31.0 | |||
| 1-120269476-A-C | c.359A>C | p.Gln120Pro | 1 | 0.64 | B | 23.5 | |||
| 1-120269497-C-T | c.380C>T | p.Ser127Leu | 1 | 0.000016 | 0.74 | D | 35.0 | ||
| 1-120269654-A-C | c.439A>C | p.Thr147Pro | 1 | 0.84 | D | 27.1 | |||
| 1-120269667-T-C | c.452T>C | p.Leu151Pro | 1 | 0.93 | D | 28.0 | |||
| 1-120269682-T-C | c.467T>C | p.Ile156Thr | 1 | 0.000018 | 0.92 | D | 29.2 | ||
| 1-120269720-A-G | c.505A>G | p.Met169Val | 1 | 0.91 | D | 24.6 | |||
| 1-120277270-A-G | c.524A>G | p.Asp175Gly | 1 | 0.97 | D | 33.0 | |||
| 1-120277272-C-G | c.526C>G | p.Pro176Ala | 1 | 1 | 0.000008 | 0.85 | D | 29.3 | 1.34 |
| 1-120277282-C-G | c.536C>G | p.Ser179Cys | 1 | 0.60 | B | 28.3 | |||
| 1-120277308-G-T | c.562G>T | p.Val188Phe | 1 | 0.000004 | 0.80 | D | 32.0 | ||
| 1-120277318-T-A | c.572T>A | p.Leu191Gln | 1 | 0.000039 | 0.66 | P | 23.3 | ||
| 1-120277365-A-T | c.619A>T | p.Thr207Ser | 5 | 0.000052 | 0.78 | P | 26.6 | ||
| 1-120277384-C-T * | c.638C>T | p.Thr213Met | 1 | 0.000008 | 0.96 | D | 34.0 | 0.13 | |
| 1-120277956-G-C | c.682G>C | p.Gly228Arg | 1 | 0.000004 | 0.86 | D | 31.0 | ||
| 1-120277956-G-T | c.682G>T | p.Gly228Trp | 8 | 31 | 0.000843 | 0.88 | D | 33.0 | 0.17 |
| 1-120277980-C-T | c.706C>T | p.Arg236Cys | 1 | 3 | 0.000060 | 0.79 | D | 34.0 | 0.19 |
| 1-120277981-G-A | c.707G>A | p.Arg236His | 1 | 1 | 0.000036 | 0.81 | D | 32.0 | 0.14 |
| 1-120278004-G-A | c.730G>A | p.Ala244Thr | 1 | 0.000028 | 0.80 | D | 26.7 | 0.23 | |
| 1-120278016-G-A | c.742G>A | p.Ala248Thr | 2 | 0.000016 | 0.88 | D | 34.0 | ||
| 1-120278040-G-A | c.766G>A | p.Gly256Arg | 1 | 0.000012 | 0.94 | D | 34.0 | ||
| 1-120278046-G-T | c.772G>T | p.Ala258Ser | 1 | 0.000008 | 0.71 | P | 28.2 | ||
| 1-120278065-A-G | c.791A>G | p.Glu264Gly | 1 | 0.54 | B | 32.0 | |||
| 1-120279791-C-A | c.847C>A | p.His283Asn | 1 | 0.94 | D | 34.0 | |||
| 1-120279801-C-T * | c.857C>T | p.Ala286Val | 1 | 0.000004 | 0.92 | D | 34.0 | 0.11 | |
| 1-120279825-G-A | c.881G>A | p.Arg294His | 1 | 0.000095 | 0.71 | P | 31.0 | ||
| 1-120279833-G-T | c.889G>T | p.Glu297Ter | 1 | 0.000004 | 43.0 | −0.08 | |||
| 1-120279844-TG-T | c.900_901T | p.Val301Phefs*6 | 1 | ||||||
| 1-120283009-G-A | c.946G>A | p.Val316Met | 1 | 0.000052 | 0.80 | P | 26.5 | ||
| 1-120283054-C-A | c.991C>A | p.Pro331Thr | 1 | 0.000004 | 0.67 | B | 24.5 | ||
| 1-120283057-T-G | c.994T>G | p.Trp332Gly | 1 | 0.67 | P | 29.7 | |||
| 1-120283093-C-T * | c.1030C>T | p.Arg344Ter | 1 | 0.000017 | 37.0 | 0.47 | |||
| 1-120283117-G-T | c.1054G>T | p.Gly352Trp | 1 | 0.53 | P | 32.0 | 0.76 | ||
| 1-120284447-T-C | c.1136T>C | p.Leu379Pro | 1 | 0.95 | D | 28.1 | 0.23 | ||
| 1-120284516-T-G | c.1205T>G | p.Leu402Arg | 1 | 0.80 | D | 26.6 | 0.47 | ||
| 1-120285493-G-A * | c.1273G>A | p.Val425Met | 1 | 0.000004 | 0.74 | P | 28.7 | 0.45 | |
| 1-120285545-C-T | c.1325C>T | p.Thr442Met | 2 | 0.000004 | 0.55 | B | 12.3 | ||
| 1-120285569-G-T | c.1349G>T | p.Gly450Val | 1 | 0.71 | B | 25.1 | |||
| 1-120285625-C-T | c.1405C>T | p.Arg469Trp | 1 | 1 | 0.000016 | 0.61 | D | 24.0 | 0.36 |
| 1-120285626-G-A | c.1406G>A | p.Arg469Gln | 1 | 3 | 0.000032 | 0.40 | P | 17.6 | 0.63 |
| 1-120285672-G-A | c.1447+5G>A | 1 | 14.0 | ||||||
| 1-120286529-G-A | c.1468G>A | p.Val490Met | 1 | 5 | 0.000142 | 0.66 | B | 27.1 | 0.55 |
| 1-120286532-C-T | c.1471C>T | p.Arg491Trp | 1 | 7 | 0.000103 | 0.53 | B | 29.7 | 0.52 |
| 1-120286568-G-C | c.1507G>C | p.Gly503Arg | 2 | 0.000012 | 0.58 | D | 23.4 | ||
| 1-120286595-T-G | c.1534T>G | p.Ser512Ala | 1 | 0.000024 | 0.64 | B | 21.3 | ||
| 1-120286599-C-G | c.1538C>G | p.Ser513Cys | 1 | 0.50 | P | 24.0 | |||
| 1-120286599-C-T | c.1538C>T | p.Ser513Phe | 1 | 0.58 | P | 25.2 | 0.85 |
All qualified variants (QVs) with gnomAD MAF < 0.001 in case and control cohorts are listed. These satisfy at least one of the following additional criteria: REVEL>0.5, Polyphen2 = P or D, Loss-of-function (stop-gain, frameshift, splicing). CADD values are shown for reference purpose only and were not used for variant qualification. A total of 29/793 (3.7%) cases and 99/17,610 (0.56%) of controls carried a single QV, resulting in two-sided FET p=1.2x10−13, OR = 6.7, 95% CI [4.2;10.3]. No cases or controls carried more than one QV. Pathogenicity of all variants present in MacTel cases was assessed by PHGDH enzymatic activity assay; results are shown in the last column. No data indicates no assay was performed, resulting in a conservative overestimate of pathogenic variants in the control cohort.
indicates variants that are causal in Neu-Laxova syndrome.