Clinical pathogenic significance: coding_sequence_variant , frameshift_variant

By SWA

 "Clinical significance: pathogenic" in the context of genetic variants, such as coding sequence variants or frameshift variants, indicates that these variants have been associated with an increased risk of disease or are directly implicated in causing a disease.

Let's break down the two types of variants:

  1. Coding Sequence Variant: A coding sequence variant occurs within the coding region of a gene, which is directly translated into a protein. Changes in this region can affect the amino acid sequence of the protein, potentially altering its function. The impact of a coding sequence variant depends on the nature of the change. For example:

    • Missense Mutation: This type of mutation results in the substitution of one amino acid for another in the protein product. Depending on the role of the altered amino acid, this can have varying effects on protein function, from benign to severely detrimental.
    • Nonsense Mutation: This results in a premature stop codon, leading to a truncated (and often nonfunctional) protein. This can have serious effects if the truncated protein loses essential functional domains.

  2. Frameshift Variant: A frameshift variant is caused by insertions or deletions of a number of nucleotides in a DNA sequence that is not divisible by three. Since genetic code is read in triplets (codons), this shifts the reading frame, altering the downstream amino acid sequence. Frameshift mutations often result in a completely different translation from the original, and typically lead to a nonfunctional protein. They are considered highly pathogenic, especially if they occur early in the coding sequence, as they can disrupt critical areas of the protein.

The determination of a variant as "pathogenic" is based on various factors including but not limited to:

  • The type of genetic change and its location in the gene.
  • The impact of the change on the structure and function of the resulting protein.
  • Evidence from scientific research linking the variant to disease.
  • Observations from clinical cases and genetic studies.

In clinical genetics, identifying a variant as pathogenic is crucial for diagnosis, prognosis, and decision-making in the management of genetic disorders. This classification is also important for genetic counseling of affected individuals and their families.

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