Table 1.
Rare functional variants identified by Sanger and targeted analysis of whole exome sequencing data for the PRRT2, PNKD, SLC1A3, SLC2A1, SLC4A4, and ATP1A4 genes in 187 patients referred for genetic testing for hemiplegic migraine, but negative for mutations in CACNA1A, ATP1A2, and SCN1A.
| Gene | Patient ID# | Locus | Transcript | Coding | Protein Change | dbSNP | MAF gnomAD (No. Alleles) | MAF gnomAD Eur NF (No. Alleles) | ClinVar (or LOVD) Annotation | SIFT a | Polyphen2 b | Mutation Taster c | Conservation d PhylopP/ PhastCons |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PRRT2 | 224 225 |
chr16:29824442 | NM_145239.3 | c.67G>A | p.Glu23Lys | rs140383655 | 0.0011 (306) | 0.0017 (219) | LB, VUS | T | B | P | 0.01/0.68 |
| 185 201 211 227 |
chr16:29825022 | NM_145239.3 | c.647C>T | p.Pro216Leu | rs76335820 | 0.007 (1737) | 0.010 (1183) | B, LB | D | D | D | 3.75/0.99 | |
| 433 | chr16:29825025 | NM_145239.3 | c.650G>A | p.Arg217Gln | rs75497546 | 0.000008 (2) | 0.0000092 (1) | D | D | P | 1.94/0.75 | ||
| 137 | chr16:29825762 | NM_145239.3 | c.988G>A | p.Ala330Thr | rs757132796 | 0.0000042 (1) | 0.0000092 (1) | D | PD | D | 2.77/1 | ||
| 261 | chr16:29825888 | NM_001256442 | c.1114C>T | p.Leu372Phe | rs565298585 | 0.000046 (13) | 0.0001 (13) | D | B | P | 0.07/0.99 | ||
| PNKD | 32 | chr2:219209684 | NM_015488.5 | c.1140_1145delTATGCA | p.Met381_His382del | rs576363906 | 0.00061 (170) | 0.0010 (135) | LB | N/A | N/A | P | N/A |
| SLC1A3 | 135 155 159 196 |
chr5:36677083 | NM_004172.5 | c.657G>C | p.Glu219Asp | rs2032892 | 0.023 (6697) | 0.0069 (887) | B, LB | T | B | P | |
| 107 | chr5:36680556 | NM_004172.5 | c.1154G>A | p.Arg385His | rs115702388 | 0.00026 (74) | 0.000061 (8) | B, LB | D | D | D | 6.24/0.998 | |
| SLC2A1 | 109 | chr1:43396789 | NM_006516.2 | c.203C>T | p.Ser68Leu | 0 | 0 | VUS | D | B | D | 3.79/0.997 | |
| 189 | chr1:43394924 | NM_006516.2 | c.929C>T | p.Thr310Ile | rs80359824 | 0 | 0 | D | D | D | 3.47/1 | ||
| 179 | chr1:43394873 | NM_006516.2 | c.972+7del (intronic) | p.Leu232PhefsTer? | rs531385270 | 0.00018 (52) | 0.00038 (50) | B, LB, VUS | N/A | N/A | D | 1.22/0.62 | |
| SLC4A4 | 136 | chr4:72205146 | NM_001098484.3 | c.313C>G | p.Pro105Ala | rs768913941 | 0.000056 (16) | 0.000092 (12) | D | B/PD | D | 6.09/1 | |
| 142 | chr4:72306423 | NM_001098484.3 | c.898A>G | p.Ile300Val | rs747159754 | 0.000053 (15) | 0.00010 (11) | T | B | D | 1.72/1 | ||
| 237 | chr4:72316925 | NM_001098484.3 | c.1229G>A | p.Gly410Glu | 0 | 0 | T | B | D | 5.76/1 | |||
| 120 179 |
chr4:72338589 | NM_001098484.3 | c.1805A>G | p.Lys602Arg | rs72650362 | 0.0022 (609) | 0.0035 (455) | D | D | D | 5.00/1 | ||
| 202 232 |
chr4:72363294 | NM_001098484.3 | c.2051A>T | p.Asn684Ile | rs35891845 | 0.0016 (443) | 0.0029 (368) | T | B | D | 2.58/1 | ||
| 128 | chr4:72399974 | NM_001098484.3 | c.2311C>T | p.Pro771Ser | rs140882617 | 0.0014 (414) | 0.0017 (231) | VUS | T | B | D | 2.55/1 | |
| 150 | chr4:72412109 | NM_001098484.3 | c.2485C>A | p.Leu829Ile | rs201643562 | 0.00036 (103) | 0.00056 (72) | VUS | D | D | D | 4.27/1 | |
| ATP1A3 | 165 | chr19:42474557 | NM_152296.5 | c.2401G>A | p.Asp801Asn | rs80356537 | 0 | 0 | Pathogenic for AHC2 | D | D | D | 4.83/1 |
| 87 | chr19:42474436 | NM_152296.5 | c.2443G>A | p.Glu815Lys | rs387907281 | 0 | 0 | Pathogenic for AHC2 | D | D | D | 4.77/1 | |
| ATP1A4 | 228 | chr1:160123000 | NM_144699.4 | c.193G>A | p.Val65Met | rs7549352 | 0.00087 (246) | 0.0015 (194) | D | PD | D | 2.14/0.95 | |
| 150 | chr1:160125005 | NM_144699.4 | c.378G>T | p.Gln126His | rs370755520 | 0.0013 (364) | 0 | D | B | D | 2.46/0.93 | ||
| 161 186 |
chr1:160125859 | NM_144699.4 | c.436G>A | p.Val146Ile | rs41288133 | 0.0022 (623) | 0.0041 (539) | T | B | P | 0.322/0 | ||
| 186 | chr1:160129260 | NM_144699.4 | c.722A>G | p.His241Arg | rs151137285 | 0.0005 (140) | 0.0010 (129) | D | B | D | 4.453/1 | ||
| 189 | chr1:160133954 | NM_144699.4 | c.787C>T | p.Arg263Trp | rs146761116 | 0.00037 (105) | 0.00063 (81) | D | D | P | 1.41/0.95 | ||
| 133 144 204 |
chr1:160133955 | NM_144699.4 | c.788G>A | p.Arg263Gln | rs76528638 | 0.014 (3969) | 0.0012 (159) | T | B | P | 0.83/0.92 | ||
| 141 188 |
chr1:160134012 | NM_144699.4 | c.845C>T | p.Thr282Met | rs144463520 | 0.001 (307) | 0.0020 (268) | D | D | D | 5.19/1 | ||
| 92 | chr1:160136403 | NM_144699.4 | c.1133C>T | p.Thr378Met | rs150693480 | 0.000045 (13) | 0.000061 (8) | D | D | D | 5.09/1 | ||
| 90 | chr1:160136459 | NM_144699.4 | c.1189G>A | p.Ala397Thr | rs147875149 | 0.000050 (14) | 0.0000077 (1) | D | D | D | 1.84/1 | ||
| 144 | chr1:160141171 | NM_144699.4 | c.1622T>G | p.Met541Arg | rs16831482 | 0.000004 (1) | 0.0000087 (1) | D | PD | D | 1.63/0.87 | ||
| 144 | chr1:160141525 | NM_144699.4 | c.1832A>G | p.Lys611Arg | rs79938119 | 0.0041 (1180) | 0.000061 (4) | B, VUS (LOVD) | D | D | D | 2.64/1 | |
| 96 | chr1:160143962 | NM_144699.4 | c.2053G>C | p.Asp685His | rs144428770 | 0.00081 (228) | 0.0016 (207) | D | D | D | 3.49/0.96 | ||
| 124 | chr1:160146341 | NM_144699.4 | c.2539A>T | p.Thr847Ser | rs145873902 | 0.00016 (45) | 0.00026 (34) | T | B | P | 1.38/0.86 |
ID#, identification number; HM, hemiplegic migraine; dbSNP, Single Nucleotide Polymorphism Database; MAF gnomAD, minor allele frequency in The Genome Aggregation Database (gnomAD); Eur NF, European Non-Finnish; LOVD, Leiden Open Variation Database v3.0; AHC2, alternating hemiplegia of childhood 2. a Sorting Intolerant from Tolerant (SIFT) variant pathogenicity prediction tool: D, damaging; T, tolerated. b Polymorphism Phenotyping v2 (Polyphen2) variant pathogenicity prediction tool: D, probably damaging; PD, possibly damaging; B, benign. c Mutation Taster variant pathogenicity prediction tool: D, disease-causing; P, polymorphism. d Nucleotide conservation scores derived from: PhyloP, values between 0 and 1, 1 high conservation; PhastCons, values between −14 and +6, >2 high, >4.88 very high conservation.