Legend

Please note that a short description of a certain column can be displayed when you move your mouse cursor over the column's header and hold it still. Below, a more detailed description is shown per column.

Allele: On which allele is the variant located? Does not necessarily imply inheritance! 'Paternal' (confirmed or inferred), 'Maternal' (confirmed or inferred), 'Parent #1' or #2 for compound heterozygosity without having screened the parents, 'Unknown' for heterozygosity without having screened the parents, 'Both' for homozygozity.

Variant Name: Trivial variant name used by clinicians

Clinical Significance: ACMG clinical significance assigned by a curator
All options:

• Pathogenic
• Likely pathogenic
• Uncertain significance
• Likely benign
• Benign

Variant Frequency: Variant Frequency among affected individuals
All options:

• Single case
• Multiple cases
• Major variant

Evidences: ACMG theses
All options:

• External source reports variant as pathogenic or likely pathogenic
• External source reports variant as benign or likely benign
• Variant allele frequency is greater then expected for the disorder
• Variant allele frequency* is >5%
• Absent in population databases or at extremely low frequency if recessive
• The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
• Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
• Missense in gene where only truncating cause disease / Silent variant in a gene where only repeat variations cause disease
• A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
• In-frame deletions/insertions in a repetitive region without a known function
• Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
• Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
• Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
• Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
• Predicted null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
• Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing
• Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
• Variant located in a mutational hot spot without known benign variations
• Variant located in critical and well-established functional domain (e.g., active site of an enzyme) without known benign variations
• Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
• Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
• Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder
• Observed in cis with a pathogenic variant in any inheritance pattern
• For recessive disorders, detected in trans with a pathogenic variant
• Lack of segregation in affected members of a family
• Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease
• De novo (without paternity & maternity confirmed) in a patient with the disease and no family history
• De novo (both maternity and paternity confirmed) in a patient with the disease and no family history
• Found in case with an alternate cause
• Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology

dbSNP ID: The dbSNP ID.

Reference: Reference to publication describing the variant

DNA change (genomic) (hg19): Description of variant at DNA level, based on the genomic DNA reference sequence (following HGVS recommendations).

• g.12345678C>T
• g.12345678_12345890del
• g.12345678_12345890dup

Effect: The variant's effect on the protein's function, in the format 'R/C' where R is the value reported by the source and C is the value concluded by the curator; '+' indicating the variant affects function, '+?' probably affects function, '+*' affects function, not associated with individual's disease phenotype, '#' affects function, not associated with any known disease phenotype, '-' does not affect function, '-?' probably does not affect function, '?' effect unknown, '.' effect not classified.

DNA change (cDNA): Description of variant at DNA level, based on a coding DNA reference sequence (following HGVS recommendations); e.g. c.123C>T, c.123_145del, c.123_126dup.

Protein: Description of variant at protein level (following HGVS recommendations).

• p.(Arg345Pro) = change predicted from DNA (RNA not analysed)
• p.Arg345Pro = change derived from RNA analysis
• p.? = unknown effect
• p.0? = probably no protein produced