08 Clinical Report Interpretation

Question 1

Are the ACMG guidelines quantitative?

Answer 1

Semi quantitative

Question 1

Why are the ACMG guidelines good?

Answer 1

Promotes consistency between labs.
Universably applicable to all clinical presentations

Question 2

What’s the arbitrary confidence value for a variant to be likely pathogenic?

Answer 2

90%

Question 3

What variants do labs not report?

Answer 3

Those that are benign or likely benign

Question 4

What classes as clinically actionable?

Answer 4

Predictive testing, carrier testing, prenatal diagnosis, druggable

Question 5

Are VUS’s reported?

Answer 5

Hot ones might be as further work may change their classification

Question 6

What’s the structure for the nomenclature for CNV finds from SNP arrays

Answer 6

array[genome build] chromosome bands (genomic coordinates) x copy number

Question 7

From Rooney Riggs CNV guidlines, what is scoring section 1?

Answer 7

Are there protein coding genes, Y or N? Discard if no

Question 8

From Rooney Riggs CNV guidlines, what is scoring section 2?

Answer 8

What genes or functional elements are in the CNV? Are any triplosensitive or haploinsufficient, or are all benign?

Question 9

From Rooney Riggs CNV guidlines, what is scoring section 3?

Answer 9

How many genes are in the CNV? Scored based on how many. Care about OMIM genes particuarly

Question 10

From Rooney Riggs CNV guidlines, what is scoring section 4?

Answer 10

A detailed evaluation of the genomic content of the CNV from the literature. Check the phenotype of any OMIM genes with the phenotype of our patient. ClinGen, DECIPHER, Panel lab, literature search.

Question 11

From Rooney Riggs CNV guidlines, what is scoring section 5?

Answer 11

Evaluation of the inheritance pattern/family history

Question 12

What do CNV scores range from and to?

Answer 12

-1 to 1

Question 13

If you find a CNV that seems to be autosomal recessive for a disease what can you do?

Answer 13

Check the exact position for any break point effects. See if the other chromosome has a variant making it “homozygous” for a change in that OMIM gene.

Question 14

When is phenotype information most difficult?

Answer 14

For prenatal cases

Question 15

Why might you test unaffected parents?

Answer 15

To identify the recurrent risk if they have more children

Question 16

Why would a genetic diagnosis matter if you knew you had Hypertrophic cardiomyopathy?

Answer 16

To establish risk to your children. So family members could get screened (genetically, and then cardiac screening). To enrol in trials that need a specific variant.

Question 17

What could you do if you had Hypertrophic cardiomyopathy but not yet a genetic test?

Answer 17

Make lifestyle changes

Question 18

Why is the specific nature of a missense variant important?

Answer 18

Because some positions are more conserved than others, and some amino acids are more similar to others.

Question 19

If a variant appears in controls at a low amount, what might you need to do?

Answer 19

Do an odds ratio, and consider the penetrance

Question 20

What can be used to find out a variant frequency amongst HCM patients?

Answer 20

Use cardio db. The atlas of cardiac genetic variation.

Question 21

What is discussed at MDTs?

Answer 21

VUS’s and incidental findings