## **Core Concept**
The question pertains to the molecular basis of sickle cell hemoglobin (HbS), a key concept in hematology and genetics. Sickle cell disease is caused by a mutation in the HBB gene that codes for the beta-globin subunit of hemoglobin. This mutation leads to the production of abnormal hemoglobin.

## **Why the Correct Answer is Right**
The correct answer, **. Substitution of glutamic acid by valine at position 6**, accurately describes the basic defect in HbS. This substitution occurs due to a point mutation in the HBB gene, where glutamic acid (coded by GAG) is replaced by valine (coded by GTG) at the sixth position of the beta-globin chain. This change from a hydrophilic to a hydrophobic amino acid causes hemoglobin to polymerize under low oxygen conditions, leading to the sickling of red blood cells.

## **Why Each Wrong Option is Incorrect**
- **Option A:** Incorrect because it does not accurately describe the substitution or the position of the mutation in the context of HbS.
- **Option B:** Incorrect as it refers to a different type of mutation or substitution not relevant to the specific defect in HbS.
- **Option C:** This option is not provided but based on the context, any other option not describing the substitution of glutamic acid by valine at position 6 would be incorrect.

## **Clinical Pearl / High-Yield Fact**
A key point to remember is that sickle cell disease is an autosomal recessive disorder. Individuals who are homozygous for the HbS allele (HbSS) have the most severe form of the disease. This condition leads to chronic hemolysis, episodes of pain, and increased risk of infections. A simple mnemonic to recall the effect of the mutation is "HbS: Sickle, Sixth position, Substitution of glutamic acid with valine."

## **Correct Answer:** . Substitution of glutamic acid by valine at position 6