Table 2. CLN3 Variants in Study Cohort.
| Symbol | Location | Sequence variation | Protein change | ACMG interpretation | Comments | Source |
|---|---|---|---|---|---|---|
| M8 | Exon 7 | c.443_445dela | p.(Val148del)a | Likely pathogenic (IV: PM1, PM2, PM3, PM4, BP5) | rs752130042 gnomAD: MAF 0.00001592; never observed at homozygous state; allele count 4 | This cohort |
| M1 | Intron 7 | c.461-3C>G | p.? | Pathogenic (II: PS4, PP1-S, PM2, PM3, PP1) | rs181995380 gnomAD: MAF 0.000004311; never observed at homozygous state; allele count 1; reported only compound heterozygous; led to abnormal transcription; homozygous in patient CIC00350a | Ku et al,20 2017 |
| M2 | Intron 7_Intron 9 | Ex8_9del of 1.02 kilobase pairs (c.461-280_677+382del) | p.? | Pathogenic (Ia: PVS1, PS3, PS4, PP1-S, PM1, PM2, PM3, PP1-M, PP1) | Reported usually as Ex7_8del (exon 1 in 5′ untranslated region omitted); most frequent | Lerner et al,11 1995 |
| M7 | Exon 12 | c.868G>T | p.(Val290Leu) | Pathogenic (IIIa: PS4, PM1, PM2, PM3) | rs3690087702 gnomAD: MAF 0.000007953; never observed at homozygous state; allele count 2 | Wang et al,10 2014 |
| M10 | Exon12 | c.883G>A | p.(Glu295Lys) | Pathogenic (IIIa: PS4, PM1, PM2, PM3, PP2, PP3) | rs121434286 gnomAD: MAF 0.00002475; never observed at homozygous state; allele count 7 | Munroe et al,21 1997 |
| M11 | Intron 12 | c.906+15C>Ga | p.?a | Uncertain significance (PM2, PM3, PP2) | Unknown rs; new splicing donor site predicted: SpliceSiteFinder: 0→73 [0-100]; MaxEntScan: 0→4.7 [0-12] | This cohort |
| M5 | Exon 13 | c.938T>Ca | p.(Leu313Pro)a | Likely pathogenic (IV: PM1, PM2, PM3, PM6, PP2, PP3) | rs141816714 gnomAD: MAF 0.00003544; never observed at homozygous state; allele count 10; PolyPhen-2: probably damaging; SIFT: damaging; MutationTaster: disease causing | This cohort |
| M3 | Exon 14 | c.1000C>T | p.(Arg334Cys) | Pathogenic (II: PS4, PM1, PM2, PM3, PS1, PP2, PP3) | rs386833694 gnomAD: MAF 0.000004011; never observed at homozygous state; allele count 1 | Munroe et al,21 1997 |
| M9 | Intron 14 | c.1056+3A>C | p.? | Pathogenic (Ia: PVS1, PS3, PS4, PP1-S, PM1, PM2, PM3, PP1-M, PP1) | rs386833698; no frequency data | Lojewski et al,22 2014 |
| M4 | Exon 16 | c.1213C>T | p.(Arg405Trp) | Pathogenic (IIIa: PS4, PM1, PM2, PM3, PP2, PP3) | rs139842473 gnomAD: MAF 0.00006742; never observed at homozygous state; allele count 19 | Wang et al,10 2014 |
| M6 | Exon 16 | c.1225A>Ga | p.(Met409Val)a | Likely pathogenic (IV: PM1, PM2, PM3, PP3) | rs776443981 gnomAD: MAF 0.00003902; never observed at homozygous state; allele count 11; PolyPhen-2: probably damaging; SIFT: deleterious; MutationTaster: disease causing | This cohort |
Abbreviations: ACMG, American College of Medical Genetics and Genomics; MAF, minor allele frequency; SIFT, Sorting Intolerant From Tolerant.
a
Novel variant.