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Table 3 Novel molecular variants identified in the study; pathogenicity status

From: New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole-exome sequencing at a national paediatric centre

Gene Variant MAF Pathogenicity statusa Genotype–Phenotype correlationb Parental results status Family history ID patient
1000 G POL 400
ACAD9 c.514G>A/p.Gly172Arg 0 0 Pathogenic Moderate in-trans Negative 15
ACAD9 c.803C>T/p.Ser268Phe 0 0 Pathogenic Moderate in-trans Negative 15
ACAD9 c.728C>G/p.Thr243Arg 0 0 Pathogenic Low in-trans Negative 53
ADAR c.3202+1G>A/p.? 0 0.0014 Pathogenic Moderate ND Affected brother 18
ADCK3 c.827A>G/p.Lys276Arg 0 0 Pathogenic High in-trans Negative 61
ADCK3 c.1702delG/p.Gly568Argfs 0 0 Pathogenic High in-trans Negative 61
AIFM1 c.1474T>C/p.Tyr492His 0 0 Pathogenic Moderate X-linked Negative 25
CDKL5 c.1942C>T/p.Gln648a 0 0 Pathogenic Moderate X-linked Negative 65
COX10 c.1030A>G/p.Met344Val 0 0.0007 Pathogenic Moderate in-trans Negative 9
COX10 c.1270dupC/p.Leu424Profs 0 0 Pathogenic Moderate in-trans Negative 9
CPS1 c.3691G>C/p.Ala1231Pro 0 0.0014 Pathogenic Low In-trans Affected sister 13
CPS1 c.1289C>G/p.Ser430a 0 0.0014 Pathogenic Moderate in-trans Affected brother 40
CPS1 c.3971_3972delT/p.1323Ile_1324Leufs 0 0.0014 Pathogenic Moderate in-trans Affected brother 40
DMD c.31+1G>A/p.? 0 0 Pathogenic Low X-linked Affected many males 38
EARS2 c.325G>C/p.Gly109Arg 0 0.0014 Likely pathogenic High in-trans Negative 7
EARS2 c.1256C>T/p.Pro419Leu 0 0 Likely pathogenic Moderate in-trans Negative 70
FBXL4 c.858+1G>T/p.? 0 0 Pathogenic High in-trans Miscarriage 3
FBXL4 c.585+5G>C/p.? 0 0 Pathogenic High in-trans Miscarriage 3
FBXL4 c.64C>T/p.Arg22a 0 0 Pathogenic Moderate in-trans Empty ovum 52
FBXL4 c.64C>T/p.Arg22a 0 0 Pathogenic Moderate in-trans Negative 55
GBE1 c.1621A>T/p.Asn541Tyr 0 0 Pathogenic Moderate in-trans Negative 14
GBE1 c.263G>A/p.Cys88Tyr 0 0 Possibly pathogenic Moderate in-trans Negative 14
GFAP c.1100G>C/p.Arg367Thr 0 0 Pathogenic Moderate de novo Negative 42
HSD17B4 c.367C>T/p.His123Tyr 0 0.0014 Pathogenic Moderate ND Affected brother 30
MECP2 c.89delA/p.Lys30Argfs 0 0.0 Pathogenic High de novo Negative 106
NDUFB8 c.432C>G/p.Cys144Trp 0 0.0014 Possibly pathogenic Moderate in-trans Negative 26
NDUFB8 c.227C>A/p.Pro76Gln 0 0 Pathogenic Moderate in-trans Negative 26
NDUFS6 c.313_315delAAAG/p.104Lys_106Thrfs 0 0 Pathogenic Moderate in-trans Affected brother 1
NDUFS6 c.334_359del26ins13/p.Glu112 fs 0 0 Pathogenic Moderate in-trans Affected brother 1
NDUFS7 c.376C>T/p.Leu126Phe 0 0 Pathogenic Moderate ND Similar symptoms in brother 75
NDUFS7 c.504G>C/p.Arg168Ser 0 0 Likely Pathogenic Moderate ND Similar symptoms in brother 75
NDUFV1 c.733G>A/p.Val245Met 0.0005 0 Pathogenic High in-trans Negative 10
NDUFV1 c.383G>T/p.Arg128Leu 0 0 Pathogenic High in-trans Negative 10
PARS2 c.1091C>G/p.Pro364Arg 0.0014 0.003 Pathogenic Moderate in trans Affected sibs 60
PARS2 c.239T>C/p.Ile80Thr 0 0 Pathogenic Moderate in trans Affected sibs 60
PC c.2381_2383delTGG/p.Val794del 0 0 uncertain Pathogenic High in-trans Affected brother 29
PC c.1487G>A/p.Arg496Gln 0 0 Pathogenic High ND Negative 71
PC c.584C>T/p.Ala195Val 0 0 Pathogenic High ND Negative 71
PDHA1 c.856_859dupACTT/p. Arg288Leufs 0 0 Pathogenic High de novo Negative 56
PDHA1 c.291G>A/p.? 0 0.0000 Uncertain pathogenic Moderate de novo Negative 68
PEX5 c.1799C>T/p.Ser600Leu 0 0 Pathogenic Low in-trans Negative 20
POLG c.2639C>A/p.Ala880Asp 0 0 Pathogenic Moderate in-trans Negative 113
PRF1 c.808_812delGGCAG/p.Gly270 fs 0 0.0000 Pathogenic Low in trans Negative 2
RARS2 c.1026G>A/p.Met342Ile 0 0 Likely pathogenic Moderate in-trans Affected brother 41
RARS2 c.622C>T/p.Gln208a 0 0.0014 Pathogenic Moderate in-trans Affected brother 41
RRM2B c.414_415delCA/p.Tyr138a 0 0.0014 Pathogenic High ND Negative 21
SBDS c.184A>T/p.Lys62a 0 0.002 Pathogenic Low in-trans PI neural tube defect 95
SCN2A c.2948T>G/p.Leu983Trp 0 0.0013 Pathogenic High de novo Negative 47
SLC25A12 c.1335C>A/p.Asn445Lys 0 0 Pathogenic Moderate in-trans Negative 24
TAZ c.684_685insC/p.227Phe_228Profs 0 0.0012 Pathogenic Low ND Negative 28
VARS2 c.1490G>A/p.Arg497His 0 0 Pathogenic Low ND Similar disease in sibs 97
  1. ND not determined due to lack of clinical data or DNA not available
  2. aPathogenicity status evaluated according to in silico prediction algorithms (CADD, MetaSVM, Polyphen2 HDIV, Polyphen HVAR, mutation assessor, LRT, MetaLR, SIFT, mutationtaster) and classified as: pathogenic—nonsense, frameshift, splicesite and missense variants with pathogenic status at least in 7 of used algorithms; likely pathogenic - missense variants with pathogenic status in 4–6 of used algorithms; possibly pathogenic—missense variants with pathogenic status <4 of used algorithms
  3. bGenotype-Phenotypecorrelationassessed by two independent specialists in clinical genetics and metabolic medicine