Table 1.
Molecular description, population prevalence, bioinformatics predictions, and pathogenicity classification according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) classification of DYNC2H1 variants identified in this study.
| Patienta | Nucleotide substitutionb | RNA substitution | Protein substitution | Variant type | Protein Domain | GnomAD | CADD score | ΔΔGc | ACMG-AMP criteria met | ACMG-AMP classification | Pubmed |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | c.6140-5A>G | r.6139_6140insATAG | p.Val2048ArgfsTer9 | Splicing | AAA + 2 | Absent | / | NE | PS3_Strong, PM2_Moderate, PM3_Moderate | LP | Not reported |
| c.9171_9174delGGAA | NE | p.(Glu3058Ter) | Frameshift | MT-binding stalk | Absent | / | NE | PVS1_VeryStrong, PM2_Moderate. PM3_Moderate | P | Not reported | |
| 2 | c.12619C>T | NE | p.(Arg4207Ter) | Nonsense | ATP-ase ring (Dynein heavy) C-terminal | 0.000004193 | 56 | NE | PVS1_VeryStrong, PM2_Moderate. PM3_Moderate | P | Not reported |
| c.6140-5A>G | r.6139_6140insATAG | p.Val2048ArgfsTer9 | Splicing | AAA + 2 | Absent | / | NE | PS3_Strong, PM2_Moderate, PM3_Moderate | LP | Not reported | |
| 3 | arr[GRCh37] 11q22.1q22.3 (99715102_103351453)x1 | - | - | Whole gene deletion | - | / | / | NE | NA | P | Not reported |
| c.6140-5A>G | r.6139_6140insATAG | p.Val2048ArgfsTer9 | Splicing | AAA + 2 | Absent | / | NE | PS3_Strong, PM2_Moderate, PM3_Moderate | LP | Not reported | |
| 4 | c.11287G>A | NE | p.(Ala3763Thr) | Missense | AAA + 6 | 0.00005360 | 34 | −0.808502 | PM1_Moderate, PM2_Moderate, PP3_Supporting | VUS | Not reported |
| c.3181C>G | NE | p.(Leu1061Val) | Missense | Stem Domain | 0.0008700 | 21.5 | 0.419578 | PM2_Moderate | VUS | Not reported | |
| 5 | c.11287G>A | NE | p.(Ala3763Thr) | Missense | AAA + 6 | 0.00005360 | 34 | −0.808502 | PM1_Moderate, PM2_Moderate, PP3_Supporting | VUS | Not reported |
| c.3181C>G | NE | p.(Leu1061Val) | Missense | Stem Domain | 0.0008700 | 21.5 | 0.419578 | PM2_Moderate | VUS | Not reported | |
| 6 | c.9171_9174delGGAA | NE | p.(Glu3058Ter) | Frameshift | MT-binding stalk | Absent | / | NE | PVS1_VeryStrong, PM2_Moderate | LP | Not reported |
| c.11453C>T | NE | p.(Thr3818Ile) | Missense | AAA + 6 | Absent | 24.9 | 1.65291 | PM1_Moderate, PM2_Moderate,PM3_Moderate | LP | Not reported | |
| 7 | c.4699C>G | NE | p.(Leu1567Val) | Missense | Stem Domain | Absent | 25.2 | 1.16155 | PM2_Moderate, PM3_Moderate, PP5_Supporting | VUS | 1 |
| c.503-9C>G | r.503_621del | p.(Arg167GlyfsTer4) | Splicing | - | Absent | / | NE | PS3_Strong, PM2_Moderate | LP | Not reported | |
| 8 | c.1151C>T | NE | p.(Ala384Val) | Missense | Stem Domain | 0.0000244 | 28.3 | 1.56786 | PM2_Moderate, PM3_Moderate PP3_Supporting | VUS | 15 |
| c.6342_6345delTCTT | NE | p. (Phe2114LeufsTer11) | Frameshift | AAA + 2 | Absent | / | NE | PVS1_VeryStrong, PM2_Moderate | LP | Not reported |
ACMG-AMP American College of Medical Genetics and Genomics-Association for Molecular Pathology, CADD Combined Annotation Dependent Depletion, GnomAD Genome Aggregation Database, LP likely pathogenetic, NA not applicable, NE not evaluated, P pathogenetic, VUS variant of uncertain significance.
aDYNC2H1 mutations have been included in the LOVD database (https://databases.lovd.nl/shared/variants/DYNC2H1/unique); LOVD individual IDs: patient 1 (#0000407149), patient 2 (#0000407151), patient 3 (#0000407152), patient 4 (#0000407195), patient 5 (#0000407195), patient 6 (#0000407196), patient 7 (#0000407197); patient 8 (#0000409854).
bNCBI Reference Sequence: NM_001377.3.
cΔΔG (ΔGmt – ΔGwt) for DYNC2H1 mutant protein.