When Genetic Changes Occur

Sample WES Report

Your child’s genetic lab results should list their type of mutation, also referred to as an Alteration.  Sample Whole Exome Sequencing Report:

When an alteration to your child’s genetic sequence is identified, this is called a “mutation.” They may also be called: alterations, variations, variants or chromosomal rearrangements.

In the summary text on your child’s lab report, there may be more information about the finding. Most laboratories will list the evidence used to classify the finding as harmful, or “disease causing.” A laboratory report may also give you information about the type of mutation that was identified.


GRIN2B Types of Gene Mutations
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Frameshift Mutations – Occur when the addition or loss of DNA causes the genetic code to shift and alters the types of amino acids that are created.  Insertions, Deletions and Duplications can all be frameshift mutations; this is dependent upon the size of the deleted or duplicated material.

  • Duplication – a piece of DNA is copied one or more times.  (Down Syndrome occurs when one has a full or partial extra copy of chromosome 21.)
  • Deletion – a piece of DNA is removed.  Deletions can be large or small and the gene function may or may not be altered, depending on the location of the piece that is missing.
  • Insertion – a piece of DNA is inserted, altering the original genetic code.

Both Missense and Nonsense mutations involve a change in one DNA base pair.

Missense – One amino acid is substituted in place of another, which changes the function of the protein. In children with epilepsy who have GRIN2B mutations, the majority have had missense mutations.  But there are several children in this group with missense mutations that have yet to have any seizures. Missense mutations can be the most difficult for a laboratory to interpret because while some missense changes can be harmful, other missense changes don’t affect the function of GRIN2B at all. Missense mutations may alter the function of the GRIN2B gene significantly, just a little bit, or not much at all.

For example: Typical Sequence: The rabbit jumped over the log. Slightly Altered Sequence: The rabbit jumped over the leg.

This sentence is slightly altered, but the meaning hasn’t changed all that much. The rabbit is still jumping over something. When you think about the GRIN2B gene, this would be equivalent to a very small change in your child’s NDMA receptor.

Significantly Altered Sequence: The rabbit juzped over the log.

This sentence is significantly altered, where we know there’s a rabbit and a log, but the word “jumped” is changed so that we cannot read it. When you think about the GRIN2B gene, this would be equivalent to a very big change in your child’s NDMA receptor.

Nonsense – Instead of substituting one amino acid for another as in the case of a missense mutation, the code stops prematurely, resulting in an incomplete protein.

Repeat Expansion – DNA sequences are grouped in 3’s.  A repeat expansion occurs when a 3 base pair of DNA is repeated more than once. These types of mutations have not been reported in people with GRIN2B mutations.

Inversion – a portion of the genetic code is reversed.

Translocation – when parts of two different chromosomes are swapped.


Chromosome US National Library of Medicine image

DNA is made up of 4 chemical building blocks – adenine, thymine, cytosine and guanine —  A, T, C and G.

In a section called either “Nucleotide Change” or “cDNA” on your child’s lab report, you may see something like this:


This indicates the nucleotide change that has taken place.  On nucleotide number 1,883 a G (guanine) has been changed to an A (adenine).

You may also see something like this on the 1st page in a section called either “Protein Change” or “Variant”:


This code indicates the protein change.  In this instance, the nucleotide change c.1883G>A has caused the Arginine(R) at amino acid position 569 to be replaced by a Histidine (H).  Arginine and Histidine are two types of amino acids.

Most lab reports will show both the DNA (“nucleic acid”) and protein (“amino acid”) changes. These can be used interchangeably.

Other important terms you may see on your reports:

  • Autosomal Dominant – indicates that an individual has a 50% chance of passing down the mutation to any offspring
  • Deleterious – harmful
  • Pathogenic – harmful
  • Benign – thought to be tolerated (not harmful)
  • VUS – variant of unclear or uncertain significance (unclear finding)
  • De Novo – the mutation is present for the first time and was not inherited from either parent.
  • Heterozygous – having dissimilar pairs of genes
  • Allele – alternative form of a gene that arises from mutation
  • Zygosity – the degree to which two alleles in a trait are similar or dissimilar (ex. Heteroxygous or homozygous)
  • Codon – a sequence of three nucleotides together that form a unit of genetic code in a DNA or RNA molecule


These are often discussed in the private Facebook groups.

Gain-of-Function versus Loss-of-Function
What do these terms mean?
From Genetics for Dummies:
Gain-of-function mutation – creates an entirely new trait or phenotype that is harmful.
Loss-of-function mutation – causes the gene to stop functioning or alters normal function.
* For a more detailed explanation of what these terms mean in relation to GRIN2B, check out About GRIN2B.

  • If your child has a missense mutation, further analysis will need to be done to determine whether the mutation is classified as gain-of-function or loss-of-function. These studies are time-intensive, requiring a scientist to create an organism with the same genetic mutation to study the effects of that particular alteration. These are called “functional studies,” which allow researchers to learn how a missense change may affect the GRIN2B gene product. These studies are not routinely performed by the laboratories where the genetic testing was completed and are usually not part of a patient’s genetics evaluation and/or workup. Your child does not need to submit any additional blood work for this study. These studies are currently being performed by the Center for Functional Evaluation of Rare Variants (CFERV) at Emory University in Atlanta, Georgia. Please check out their website for details on how to submit a gene report for analysis. Please note – it can take up to 6 months for this to be determined.
  • If your child’s mutation is anything other than missense, it is assumed to be a loss-of-function mutation.

Why are all these terms important to know?

As you can see, there are many different types of mutations, which all contribute to how our children are affected.  The location of a mutation can provide insight into the pathogenicity of a mutation (whether an alteration in the gene sequence is harmful or not), and it can be helpful to talk with your child’s genetic counselor about where the mutation is located within the gene. For example, changes, or alterations in the genetic sequence may be tolerated at the very end of the GRIN2B gene (also called the “tail” of the gene’s sequence). This means that not all changes to the GRIN2B gene are considered to be harmful.

A child with a GRIN2B deletion may present differently from a child with a missense mutation.  And two children, both with missense mutations, may be similar, but have a lot of differences depending on if one has a gain-of-function and one has a loss-of-function. Because of the many different ways the GRIN2B gene can be altered, there is a wide spectrum in the ways our children are affected.

There has been recent discussion in the GRIN2B community about the use of the drug, Memantine. Memantine is normally used in Alzheimer’s patients. The research thus far is showing that the use of Memantine would only potentially work on individuals with a Gain-of-function mutation, not loss-of-function. For more info on upcoming potential clinical trials regarding the usage of Memantine in GRIN2B patients, please check out our News page.