**Core Concept**
Sickle cell disease is a genetic disorder caused by a point mutation in the HBB gene encoding the beta-globin subunit of hemoglobin. This mutation leads to the production of abnormal hemoglobin, known as sickle hemoglobin (HbS), which causes red blood cells to adopt a sickle shape under low oxygen conditions.

**Why the Correct Answer is Right**
The mutation responsible for sickle cell disease is a substitution of glutamic acid (E) with valine (V) at position 6 of the beta-globin chain, resulting in the HbS protein. This substitution leads to polymerization of HbS under low oxygen conditions, causing red blood cells to become rigid and adopt a sickle shape. The resultant sickled cells are more prone to hemolysis and vaso-occlusion.

**Why Each Wrong Option is Incorrect**
**Option A:** This option is incorrect because it does not specify the correct mutation responsible for sickle cell disease.
**Option B:** This option is incorrect because it does not mention the correct substitution of glutamic acid with valine at position 6 of the beta-globin chain.
**Option C:** This option is incorrect because it refers to a different genetic disorder, such as beta-thalassemia.

**Clinical Pearl / High-Yield Fact**
It's essential to remember that sickle cell disease is an autosomal recessive disorder, meaning that a person must inherit two copies of the mutated gene (one from each parent) to express the disease. Carriers of the mutated gene, who have one normal and one mutated copy, are generally asymptomatic but can pass the mutated gene to their offspring.

**Correct Answer: B. Valine substitution at position 6 of the beta-globin chain.**