Variant Classification

For a reliable genetic interpretation
Variant Classification

A critical step in the diagnostic process

Classification of variants is the basis of a correct genetic diagnosis, being that it is crucial for the clinical experts when making decisions, having an impact on the treatment and the genetic assessment of the patients and their families.

Having up to date information from both our own and international genetic databases such as the medical-scientific bibliography is vital to be able to reach a reliable and accurate conclusion with regards to the possible pathogenicity of each genetic variant. Incorrect classification could lead to an incorrect diagnosis of a patient and even have serious consequences on the stratification risk for family members.

At Reference Laboratory we classify the variants based on the recommendations from the American College of Medical Genetics and Genomics (ACMG). It relates to a system of qualitative evaluation with 28 classification criteria, those of which are assigned major or minor pathogenicity or benignity (very solid/solid/moderate/supported). In order to have a certain degree of flexibility the possibility exists to increase or decrease the weight of the evidence following the criteria and experience of the professional.

Using this guide the variants can be classified into 5 classes:

Benign variant (Class 1)

Likely benign variant (Class 2)

Variant of uncertain significance (Class 3)

Likely pathogenic variant (Class 4)

Pathogenic variant (Class 5)

On our result reports, we only report on variants which, based on current information, are considered to be pathogenic, probably pathogenic, or of significant clinical uncertainty and that are related to the suspicion of clinical diagnosis. When required, the complete list of variants identified is available upon request.

As well as following the recommendations of ACMG, we evaluate the variants according to the evidence available on:

  • RefLab Database®, our database of genetic variants.
  • Database of population frequency: 1000 Genomes, dbSNP, ExAC and gnomAD.
  • Clinical databases: OMIM, Genereviews, Orphanet, Human Gene Mutaon Daȁtabase (HGMD), ClinVar, LOVD and Human Phenotype Ontology (HPO).
  • Databases specific to the illness.
  • Algorithyms ‘in silico’ of functional prediction and of protein splicing: Mutation Taster, SIFT, PolyPhen-2, Human Splicing Finder, MaxEntScan, NNSplice.
  • Relevant bibliography: PubMed and scientific literature.

Variant reclassification service

The field of clinical genetics is constantly growing and new genes, new variants and new evidence related to previously discovered variants are discovered every day. At Reference Laboratory, we are conscious of how fast these advances evolve and we believe that offering quality and up to date information is vital so that health professionals are able to make informed decisions. This is why we carry out proactive monitoring of the variants detected in our genetic studies. We are aware that the understanding of new evidence can help us to establish a better genotype-phenotype correlation, especially for non-conclusive variants (likely pathogenic, uncertain significance, or likely benign).

Our variant reclassification system is based on the checking of data available in new publications and updates on Reflab Database® and external databases (clinics, population frequency, or specific to an illness) As soon as new genetic evidence is available, we share it with the prescribing health professional.

Studies of family segregation or the identification in a new patient of a previously identified variant in another of our cases are also an important method for possible reclassification of a variant.

RefLab Database®

Detailed information on millions of
gene variants validated by our experts

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