Table 1
Nomenclature of genetic variants. A definition and examples are reported for the main genetic variants described in the manuscript. A: adenine; C: cytosine; G: guanine; T: thymidine. In the absence of a universal consensus on nomenclature, we adopt the following operational definitions for this review: small insertions, deletions, or combined changes involving fewer than 50 base pairs (bp) are referred to as “del,” “ins,” or “delins”; changes involving more than 50 bp are referred to as copy number variants (CNVs).
| GENETIC VARIANT | DEFINITION | EXAMPLE |
|---|---|---|
| Single nucleotide variant (SNV) | A variant involving one nucleotide, which can be replaced by one other nucleotide, resulting in coding for a different amino acid (missense variant) or in a stop codon (nonsense variant) | c.2345A>C (nucleotide in position 2345 (A) is substituted with a C) |
| Deletions and/or insertions (del, ins, delins or indels) | Insertions and/or deletions of ≥1 consecutive nucleotides in genomic DNA | Ins: c.2345_2346insG (G inserted between position 2345 and 2346); Del: c.2345_2346delAC (nucleotides between position 2345 and 2346 (AC) are deleted); Delins: c.2345_2346delinsTG (Nucleotides from position c.2345 to c.2346 (AC) are deleted and replaced by TG) |
| Duplications | A copy of ≥1 nucleotides inserted 3’ of the original sequence | Dupl: c.2345_2349dupl (nucleotides between 2345 and 2349 are duplicated) |
| Repeat expansions | A sequence where ≥1 nucleotides is present several times, one after the other, in a region of the DNA prone to expand (e.g., repeats of 3 nucleotides “triplets”, of 4 “quadruplets”, of 5 “pentanucleotides” and so on) | c.2345–2405CAG[45]GGA[1] (between nucleotide 2345 and 2405 there are 45 CAG repeats and 1 GAA repeats) |
| Copy number variants (CNV) | Large stretch of DNA that can be deleted, inserted or amplified – not defined precisely by size, but usually covering at least an exon of a gene or 1,000 nucleotides or more | PRKN: exon 2 del (exon 2 of the PRKN gene is deleted) |
| Structural variants (SVs) | Complex rearrangement of the DNA through inversion, translocation, gene fusions or CNV | Gene inversion: c.108_205inv (nucleotide between position 108 and 205 are inverted) |
Figure 1
Schematic representation of genetic changes and appropriate genetic tests. The four sections of the figure depict the most important genetic variants that can be found in hyperkinetic movement disorders (upper part of the figure) and the appropriate tests to assess each genetic change (lower part of the figure). MLPA: Multiplex ligation-dependent probe amplification; NGS: next generation sequencing; WES: whole exome sequencing; WGS: whole genome sequencing. Figure created with BioRender.
Figure 2
ACMG variant classification framework: categories of evidence contributing to pathogenic vs. benign interpretation. Each type of evidence shown in the figure may support either pathogenicity (green) or benignity (red), depending on the data available.
Population data support pathogenicity when the variant is absent or extremely rare in databases such as gnomAD or ExAC (e.g., PM2), and benignity when the variant is too frequent to be compatible with disease (e.g., BA1, BS1). Segregation analysis supports pathogenicity when the variant co-segregates with disease within affected family members (PP1), and benignity when found in unaffected relatives (BS4). In silico prediction tools such as SIFT, PolyPhen-2, and CADD support pathogenicity when multiple tools predict a damaging effect (PP3), and benignity when predictions are consistently benign (BP4). Functional studies provide support for pathogenicity when validated assays show loss of function or abnormal splicing (PS3), and support for benignity when normal function is demonstrated (BS3). Allelic data support pathogenicity when other known pathogenic variants affect the same residue or domain (PM5), and benignity when the variant occurs in -trans (on the other allele) with a pathogenic variant but the individual is unaffected (BP2). Phenotype consistency supports pathogenicity when the patient’s phenotype strongly matches the gene-disease relationship (PP4), and benignity when inconsistent or unrelated (BP5). De novo data contributes to pathogenicity when confirmed by parental testing in a consistent phenotype (PS2), while isolated or unconfirmed de novo findings in unrelated phenotypes may provide weak or no support. Other database or case-level data support pathogenicity when the variant is consistently reported as pathogenic in databases like ClinVar or HGMD (PP5), and benignity when consistently reported as benign without conflicting evidence (BP6). Adapted from Richards et al., Genet Med 2015, and updates by ClinGen SVI Working Group, Genet Med 2020.