Interpretation of a genetic variant

Accessing and Understanding Data
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In this post I would like to explain the way to read a genetic laboratory report and its interpretation.

For this purpose I will use an example of a commercial laboratory report:

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The genetic variant " c.1561G>A (p.Gly521Arg)" is a specific change in the DNA sequence of the PANK2 gene. Let’s break down each part:

  • Gene: PANK2: a gene know to produce Neurodegeneration with brain iron accumulation (NBIA). In the new MDS classification this group of conditions were reclassified according to their predominant phenotype. They propose the name DYT-PANK2-(NBIA), as It’s main phenotype is dystonia, but could be accompanied by other movement disorders such as parkinsonism. Actually, it is included under the category of “other diseases with parkinsonism”.

  • Variant: c.1561G>A: This part describes the specific change in the DNA sequence. The “c.” stands for “coding sequence,” and “1561” is the position of the change in the DNA sequence of the gene. “G>A” indicates that a Guanine (G) is replaced by an Adenine (A) at this position. p.Gly521Arg: This part describes the effect of the DNA change on the protein produced by the gene. The “p.” stands for “protein.” “Gly521Arg” indicates that at position 521 in the protein, the normal Glycine (Gly) is replaced by Arginine (Arg).

  • Zygosity: heterozygous (one copy of the pathogenic variant), meaning that in a recessive condition, it is not a disease causing genetic variant.

  • Pathogenicity: This means that the variant is known to cause disease.

If the pathogenicity is not described in the report, it can be found in databases such as ClinVar, which is a freely accessible, public archive of reports of the relationships among human variations and phenotypes.

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I thought that was very informative! Thanks for the post!

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Very interesting! @psaffie are there other databases like ClinVar that you commonly use or would recommend to others? If there are multiple, would be curious if you could talk a bit more about the differences between them and why you might visit one over another?

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Josh, yours is a really tricky question, because there is a lot of platforms, and each one has different characterstics, that makes them complementary. I am really interesting in developing guidelines to work on this specific topic, within diseases. For example, which datebases are better for PD, or even, for each PD related gene. For example, for GBA1, you have the GBA1 browser that is the more updated place to look for GBA1. And it is also realted to @gdp22 post on GBA1.
So, I don´t have a straight forward answer, but I can tell you that is something that I am working on and hope to have a better answer for you in the next few months.

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Awesome, thanks! Would love to hear more about this as it progresses – are you planning to publish on this or more just a personal learning project?

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I think as a part of my phD project. Probably will begin personal, and then if it all goes good, It could be published

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As a clinician, I also rely on my colleagues who are geneticists or genetic counselors to determine pathogenicity of a variant. If I encounter a variant and I cannot establish it’s pathogenicity using ClinVar, Pubmed, or other web based resources, I ask for help from these experts who often are able to guide me and give me some estimation of pathogenicity depending on other similar variants where pathogenicity is known. Thanks for the interesting post!

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That is certainly the best scenario, but sadly, we don´t have neurogeneticist in Chile. The geneticist are scarce, and more into cancer or child genetic disorders. I know that it is not the same in Brazil, where they have a huge development in this field, and was one of the reasons for doing my phD there.