SU3.3

Question 1

What international standard provides a uniform way to describe DNA, RNA, and protein sequence variants?

Answer 1

The Human Genome Variation Society (HGVS) nomenclature.

Question 2

What is the basic structure for describing a sequence variant using HGVS nomenclature?

Answer 2

Reference_position_change.

Question 3

In HGVS nomenclature, what does the prefix ‘g’ denote as the reference sequence?

Answer 3

Genomic DNA (gDNA).

Question 4

What type of reference sequence is indicated by the prefix ‘c’ in HGVS nomenclature?

Answer 4

Coding DNA (cDNA), derived from mRNA.

Question 5

In HGVS nomenclature, what does the prefix ‘p’ signify?

Answer 5

The reference sequence is a protein.

Question 6

Which HGVS prefix is used to describe a variant in non-coding DNA?

Answer 6

The prefix ‘n’.

Question 7

What does the prefix ‘m’ indicate in HGVS nomenclature?

Answer 7

The reference sequence is mitochondrial DNA.

Question 8

Which reference sequence is denoted by the prefix ‘r’ in HGVS nomenclature?

Answer 8

RNA.

Question 9

In HGVS nomenclature for DNA, the symbol _____ represents a substitution.

Answer 9

>

Question 10

What type of DNA change is represented by ‘del’ in HGVS nomenclature?

Answer 10

A deletion.

Question 11

In HGVS nomenclature, what does ‘ins’ signify on a DNA level?

Answer 11

An insertion.

Question 12

What type of DNA variant is described by ‘dup’ in HGVS nomenclature?

Answer 12

A duplication.

Question 13

The HGVS term ‘delins’ is used to describe what type of genetic variant?

Answer 13

A deletion-insertion, where one or more nucleotides are replaced by one or more other nucleotides.

Question 14

In HGVS nomenclature, the term _____ is used to describe an inversion.

Answer 14

inv

Question 15

How are intronic variants, relative to the coding sequence, denoted in HGVS nomenclature?

Answer 15

With a plus or minus sign followed by the nucleotide position, such as ‘+1’ or ‘-2’.

Question 16

On the protein level, what does the HGVS notation ‘fs’ indicate?

Answer 16

A frameshift mutation.

Question 17

What does the asterisk symbol ‘*’ signify in HGVS nomenclature for proteins?

Answer 17

A termination codon (stop codon).

Question 18

In protein variant nomenclature, ‘ext’ denotes what type of change?

Answer 18

An extension of the protein sequence.

Question 19

In the HGVS string NM_000492.3:c.145_147delinsTGG, what does NM_000492.3 represent?

Answer 19

A unique permanent sequence identifier from a database like GenBank.

Question 20

Analyse the notation c.145_147delinsTGG. What does this describe?

Answer 20

On the coding DNA level, nucleotides from position 145 to 147 have been deleted and replaced with the sequence TGG.

Question 21

What change at the protein level is described by the notation p.Arg49Trp?

Answer 21

The amino acid Arginine at position 49 has been replaced with Tryptophan.

Question 22

What does the clinical reporting category ‘Pathogenic’ indicate about a genetic variant?

Answer 22

There is strong evidence that the variant causes disease.

Question 23

What is the definition of a ‘Likely pathogenic’ variant in a clinical report?

Answer 23

There is a high probability that the variant causes disease.

Question 24

What does the term ‘Variant of Uncertain Significance’ (VUS) mean in a genetic test report?

Answer 24

There is insufficient evidence to determine whether the variant is disease-causing or benign.

Question 25

How is a 'Likely benign' variant defined in clinical reporting?

Answer 25

There is a high probability that the variant does not cause disease.

Question 26

What does the classification 'Benign' signify for a genetic variant?

Answer 26

There is strong evidence that the variant has no clinical impact.

Question 27

What is the general expectation regarding the clinical impact of most Variants of Uncertain Significance (VUS)?

Answer 27

Most VUS are expected to be benign.

Question 28

What is a major ethical implication for a patient when a VUS is reported?

Answer 28

Reporting a VUS can cause the patient great anxiety.

Question 29

What is the primary ethical argument against the non-reporting of a VUS?

Answer 29

Not-reporting a VUS eliminates the possibility of future management if the variant is later reclassified as pathogenic.

Question 30

What types of mutations are more likely to be considered pathogenic when evaluating a VUS?

Answer 30

Truncating, frameshift, or nonsense mutations.

Question 31

Besides truncating mutations, what other type of missense mutation may indicate pathogenicity for a VUS?

Answer 31

A non-conservative missense mutation.

Question 32

In assessing a VUS, what is the significance of a variant occurring in a protein's active centre or binding site?

Answer 32

A change in such a critical functional region increases the likelihood of pathogenicity.

Question 33

How can analysing a variant's inheritance pattern in a family help clarify a VUS?

Answer 33

Observing the segregation pattern can help determine if the variant tracks with the disease in the family.

Question 34

If a genetic variant is found in more than 1% of the population, what is it most likely to be?

Answer 34

A benign polymorphism, not a pathogenic mutation.

Question 35

What is a key ethical challenge that arises from discovering incidental findings?

Answer 35

They raise complex ethical implications regarding whether, and how, to disclose information unrelated to the initial test.

Question 36

Define 'Incidental Findings' in the context of genetic and genomic testing.

Answer 36

Genetic variants identified that are unrelated to the primary clinical reason for performing the test.

Question 37

Why is stringent validation required for high-volume sequencing data?

Answer 37

The large quantity of data generated demands rigorous checks to ensure accuracy and reliability.

Question 38

How can established datasets be used to validate new sequencing data?

Answer 38

By comparing the new data against trusted, well-curated datasets to check for consistency and accuracy.

Question 38

A common validation strategy in sequencing involves using _____ and technical replicates.

Answer 38

biological

Question 39

What is one method that can be used to confirm results from an RNA-seq experiment?

Answer 39

A different method, such as quantitative PCR (qPCR).

Question 40

How does comparing data from different sequencing platforms contribute to validation?

Answer 40

It helps to confirm that the findings are robust and not an artefact of a single technology (e.g., comparing Illumina vs Oxford Nanopore).