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Table. 3.

Table. 3.

Significant variants with pathogenicity classification detected using the NEOseq_ACTION panel

Case No. Gene symbol Transcript Nucleotide change Amino acid change Zygosity Variant classification by MedyPatho Segregation Clinical validation Final classification ACMG evidences*
P2 GALNS NM_000512.4 c.319G >A p.Ala107Thr Het LP Trans Serum galactose-6-sulfatase 0.37 nmol/17 hr/mg protein (ref, 18.6–61.8) LP PM2, PM3, PP3, PP5
GALNS NM_000512.4 c.451C >A p.Pro151Thr Het LP LP PM1, PM2, PM5, PP3, PP5
P5 ACADS NM_000017.2 c.1031A >G p.Glu344Gly Het LP Not done Serum C4 1.995 μmol/L (cut off, 0.41) LP PM1, PM2, PP3, PP5
ACADS NM_000017.2 c.164C >T p.Pro55Leu Het LP LP PS3, PM2, PP5
P6 PCCA NM_000282.3 c.1846-2A >G p? Het LP Trans Urine propionylglycine 80.0 (ref, not detected) LP PVS1, PM2
PCCA NM_000282.3 c.938G >C p.Arg313Pro Het VUS LP PM2, PM3, PM5, PP3
P10 PAH NM_000277.1 c.975C >G p.Tyr325* Het P Not done Serum phenylalanine 163 μmol/L (ref, 13–91) P PVS1, PM2, PP5
PAH NM_000277.1 c.158G >A p.Arg53His Het VUS VUS BS2, PM5
P14 SLC25A13 NM_014252.3 c.852_855delTATG p.Met285Profs*2 Het P Not done Serum citrulline 378 μmol/L (ref, 8–36) P PVS1, PM2, PP5
SLC25A13 NM_014252.3 c.1177+1G >A p? Het P P PVS1, PM2, PP5
P25 ACADM NM_000016.4 c.1189T >A p.Try397Asn Het LP Trans Serum C6 0.145 μmol/L (cut off < 0.1), C8 0.26 μmol/L (cut off < 0.18), C10:1 0.16 μmol/L (cut off < 0.13) LP PM2, PM5, PP2, PP3, PP4, PP5
ACADM NM_000016.4 c.1231G >T p.Val411Leu Het VUS LP PM2, PM3, PP2, PP4
P36 ACADM NM_000016.4 c.1189T >A p.Tyr397Asn Het LP Not done Serum C6 0.64 μmol/L (cut off < 0.1), C8 1.59 μmol/L (cut off < 0.12), C10:1 0.45 μmol/L (cut off < 0.08) LP PM2, PM5, PP2, PP3, PP4, PP5
ACADM NM_000016.4 c.91C >T p.Arg31Cys Het VUS LP PM2, PM5, PP2, PP4, PP5
P40 MCCC2 NM_022132.4 c.838G >T p.Asp280Tyr Het LP Not done Urine 3-hydroxyisovaleric acid 1,731.1 mmol/mol Cr (ref, < 18) LP PM2, PP2, PP3, PP4, PP5
MCCC2 NM_022132.4 c.1342G >A p.Gly448Arg Het VUS LP PM2, PP2, PP3, PP4, PP5
P41 PREPL NM_006036.4 c.1979_1980del p.Leu660Glnfs*9 Het LP Trans Repetitive nerve stimulation test, insignificant P PVS1, PM2, PM3
PREPL NM_006036.4 c.1747-9_1747del p? Het LP P PVS1, PM2, PM3
P45 HBA2 NM_000517.4 c.427T >C p.*143Qext*31 Hem LP Not done Not done LP PM2, PM3, PM4
P46 PHKA2 NM_000292.2 c.1246-2A >G p? Hem LP Not done GOT/GPT 59/49 IU/L (ref, 1–40/1–40) LP PVS1, PM2
P72 ACADS NM_000017.2 c.164C >T c.Pro55Leu Hom LP Not done Serum C4 0.805 μmol/L (ref, < 0.41) LP PS3, PM2, PP5
P74 ACADS NM_000017.2 c.1031A >G p.Glu344Gly Het LP Not done Serum C4 0.905 μmol/L (ref, < 0.41) LP PM1, PM2, PP3, PP5
ACADS NM_000017.2 c.1130C >T p.Pro377Leu Het LP LP PM1, PM2, PP3, PP5
P83 ACADS NM_000017.2 c.1031A >G p.Glu344Gly Hom LP Not done Serum C4 1.965 μmol/L (ref, < 0.41) LP PM1, PM2, PP3, PP5
P111 PAH NM_000277.1 c.1068C >G p.Tyr356* Het P Not done Serum phenylalanine 173 μmol/L (ref, 25–74) P PVS1, PM2, PP5
PAH NM_000277.1 c.158G >A p.Arg53His Het VUS VUS BS2, PM5

*All variants were assessed based on the ACMG or Association for Molecular Pathology guidelines [17]; Initial classification using MedyPatho was changed at final classification; Given the high homology between HBA1 and HBA2 and that common deletions account for 85% of pathogenic variants in alpha thalassemia, Sanger sequencing and multiplex ligation probe amplification were performed to confirm the variant. This patient had a heterozygous common–SEA deletion; thus, the zygosity of the c.427T>C variant was determined to be hemizygous.

Abbreviations: ACMG, American College of Medical Genetics and Genomics; Het, heterozygous; Hem, hemizygous; Hom, homozygous; LP, likely pathogenic; P, pathogenic; VUS, variant of unknown significance; ref, reference range.

Ann Lab Med 2023;43:280~289 https://doi.org/10.3343/alm.2023.43.3.280

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