HUGE Lecture 15 10/20/2026

How do you test for cystic fibrosis

Sweat chloride test- they have more salt in their sweat than most people

What are the variant classifications

• Pathogenic

• Likely pathogenic

• Uncertain

• Likely benign

• Benign

Pathogenic variant

definitely causes the disease

Likely Pathogenic variant

>90% sure causes the disease

Uncertain variant

there’s conflicting or not enough data

Likely benign variant

>90% sure doesn’t cause the disease

Benign

definitely doesn’t cause the disease

How are all genetic variants initially considered

uncertain until proven pathogenic or benign

What are the 5 evidences to a variant scientist’s classification

• Gene-disease relationship

• Population information

• Predicted effect on the protein

• Patient and family data

• Functional or experimental data

Gene-disease relationship

Do variants in the gene cause the condition

What are the mechanisms of gene variant-disease

• Normal protein

• Loss of function protein

• Dominant negative

• Gain of function

Population information

How common is a variant in healthy and disease populations

What database can you use for population information

ClinVar and GNOMAD- has allelic frequency information separated by ancestry groups and ethnicity

Predicted effect on the protein

predicted impact on structure/function

What can predicted effect on the protein be

truncating or missense mutations and effect depends on location in critical domains

Where is patient and family data gathered

case reports and clinical databases

What to consider with patient and family data

• does the variant track with disease in families

• does the variant appear in multiple affected individuals

What does functional or experimental data tell us

has anyone tested what this variant does in the lab