Clue 1: Orient yourself
Which card has the strongest review trail?
Use the labels and the picture's left-to-right, near-to-far, or before-and-after order. Name only what you can point to.
The question
Which card has the strongest review trail?
Why it matters: Genetic results can change family counseling and research decisions. They must be interpreted without turning risk into destiny or an uncertain variant into a diagnosis. Today you practice the professional reasoning behind that work: Variant interpretation combines clinical assertions, population frequency, molecular consequence, and evidence quality.
On your WebXam
Classifying a variant as pathogenic, benign, or VUS from database evidence
For life
To find the cause, change one thing and watch what changes.
Principle: Same look, different cause
Five principles we return to
Having it is not using it
Same instructions, different switches
Same look, different cause
Change one thing and watch
Boss or doorman?
Decides the result or only allows it
Held down, not gone
Remove the brake and it returns
Many roads, one ending
One result can begin many ways
Try the everyday version first
A library catalog card needs several trust signals
A catalog record says what a library has recorded about a book. Readers still check the title, author, edition, and review status before trusting that it matches their question.
Do not jump to the biology yet. Treat the picture as a small system. Track its parts, follow one change at a time, and keep more than one explanation open until the picture supplies a way to separate them.
Clue 2: Trace one change
Why does a rare book not have to be harmful?
Follow one object, stage, or path. Point to the first place where the situation changes instead of jumping to the ending.
Clue 3: Keep the cause open
What should happen when reviewers disagree?
List more than one explanation that still fits. Name the extra observation that would help you separate those possibilities.
Now inspect the illustration
Work from the visible evidence. A useful answer names the part of the picture that supports it and leaves unknown causes open.
- 1Which card has the strongest review trail?
- 2Why does a rare book not have to be harmful?
- 3What should happen when reviewers disagree?
Tier 1 check
Finish with the everyday model
Use the everyday picture to answer today's question in plain words: Which card has the strongest review trail?
You can complete today's required check without opening the technical details below.
Ready for the real names? Optional tier 2
Technical rules and limits
Rule 1: Read classification with review status.
Rule 2: Check population frequency and condition match.
Rule 3: Treat uncertain and conflicting evidence honestly.
Where the analogy stops: Evidence databases change as new results arrive. They are not final verdicts.
Carry the previous idea forward
IRF6 encodes a transcription factor that changes cell behavior by controlling other genes.
Today's technical takeaway
Variant interpretation combines clinical assertions, population frequency, molecular consequence, and evidence quality.
Now map the same rules onto biology
Read a ClinVar-style IRF6 record
Catalog claim
Clinical significance
Review trail
Submission criteria and review status
Circulation count
Population allele frequency
Educational illustration, not a clinical photograph or diagnostic result. Use the labeled evidence cards and claim ceiling.
Mateo's case file: evidence supplied in this lesson
GEN06-E1
ClinVar stores submitted variant-condition classifications and review status.
Why it matters: A classification must be read with its evidence level.
GEN06-E2
A pathogenic IRF6 assertion should match an IRF6-related condition and supporting evidence.
Why it matters: Condition context matters.
GEN06-E3
A common population variant is unlikely to cause a rare fully penetrant syndrome by itself.
Why it matters: Frequency constrains pathogenic claims.
Make the clinical decision
You are the variant-review trainee.
An IRF6 record says pathogenic but has one old submission and no assertion criteria; another lab calls it uncertain.
AReport the conflict and seek stronger current evidence.
BTreat the word pathogenic as final without review context.
CCall every rare variant disease-causing.
Choose the report language and cite review-status plus frequency rules.
Evidence required
GEN06-E1 + GEN06-E2 Claim ceiling
You may summarize database evidence. You may not independently diagnose from a weak or conflicting record.Go deeper Optional tier 3
Everything required for today is above. Open these only if you want the explainer, source trail, or download files.
The everyday model and Tier 1 check are the complete required path for this lesson.
Use these checks to keep your place. They are not turned in through the portal.
Check off as you finish
- Worked through the everyday picture and answered its three questions.
- Completed the Tier 1 check in plain words.
Turn in: Genetics lesson 6: Looking Up a Variant
Go to Schoology to turn this in.
Submit one PDF. Put your first and last name in the document header. Name the file: FirstName LastName - Assignment Title - YYYY-MM-DD.pdf.
Open Schoology PDF upload helpIf you cannot get in, see Mr. Mendoza. Do not skip the work.
Optional legacy technical materials Open only if you want the original notes, vocabulary, artifact, and CER work
Before this page, you should know
- IRF6 is the gene, and it makes a -factor .
- A variant is a change in DNA, and not all variants are harmful.
If not, review
Today's new idea is only
Today's new idea is only this: a database call (pathogenic, benign, or VUS) is built from the weight of evidence and can change as new evidence comes in.
Goal: Students will navigate ClinVar and OMIM and classify a variant entry as benign, pathogenic, or a .
Know by the end
- ClinVar (NIH) stores individual DNA variants and the conditions they have been linked to, each with a clinical-significance call.
- OMIM catalogs genes and the inherited diseases they cause; IRF6 maps to two diseases, (#119300) and popliteal pterygium syndrome (#119500).
- The three clinical-significance calls are pathogenic, benign, and .
- A change common in healthy people is usually benign, while a rare change concentrated in affected families is a red flag; calls can change as evidence accumulates.
- gnomAD (the Genome Aggregation Database) is the healthy-population yardstick: it reports how often a variant appears in tens of thousands of mostly healthy people, so a damaging change that is absent there is a red flag for pathogenic.
1
Two databases
Model start: ClinVar stores individual variants and their condition links; OMIM stores the link between a gene and the diseases it causes.
- ClinVar (NIH) stores individual DNA ____ and the conditions they have been linked to.
- OMIM stores the link between a ____ and the named diseases it can cause; IRF6 maps to VWS and PPS.
2
The three calls
- Pathogenic: strong evidence the change ____ disease (example IRF6 R84C, linked to PPS).
- Benign: evidence the change does NOT cause disease, often because it is ____ in healthy people (example IRF6 V274I).
- : not enough evidence yet to call it either way.
3
How a call is built
- A call is built from ____ (frequency in patients versus healthy people, family patterns, lab tests, and prior reports).
- Calls can ____ as new evidence comes in; a VUS today can become pathogenic or benign tomorrow.
Everything you need for today is on this page. These links are optional.
What to read
Read the abstract of Leslie et al. (2012) on IRF6 variants. Notice the same gene shows up in both Van der Woude and the more severe popliteal pterygium syndrome. Leslie EJ, et al. 2012. IRF6 variants in VWS and PPS. Genet Med. [PMID:23154523]
Why this source matters
It shows real IRF6 variants and the conditions they cause, which is exactly what a ClinVar entry summarizes one variant at a time.
Words to unlock first
Reading moves
- Skim the title and abstract first to get the gist.
- Circle the one sentence that states the main claim.
- Box the evidence the authors give for that claim.
- Mark one sentence that confuses you, and move on.
Stop point
You do not need the statistics or every variant in the tables. Stay with the idea that a call rests on the weight of evidence.
Your output
Write one claim-evidence sentence about why a brand-new, never-reported IRF6 variant should be classified as a VUS right now.
Where this fits
Tested on (Ohio WebXam)
Genetics of Disease · 072130
PLTW lesson
MI · Genetics domain · Unit 2 How to Screen Your Genes, 2.1 Genetic Testing and Screening
WebXam domain
Molecular and Genetic Technology
Evidence to produce
Given a patient's IRF6 change reported in no database, write the call you would record right now using the three categories and name the one piece of evidence you would most want next to move it off uncertain.
Lab / skill
Medical Interventions (MI) · Principles of Biomedical Science (PBS)
Everything required for today's decision is already in the case file and plain-language explainer. The links below are original papers and database records for teachers and advanced readers, not assigned student reading.
- Kondo S, et al. 2002. IRF6 mutations cause VWS and PPS. Nat Genet. [PMID:12219090]
- Leslie EJ, et al. 2012. IRF6 variants in VWS and PPS. Genet Med. [PMID:23154523]
- ClinVar (NIH), query gene IRF6
- OMIM IRF6 (#607199); VWS1 #119300; PPS #119500 (professional database; use MedlinePlus Genetics if blocked)
- gnomAD (Broad Institute), gene IRF6: allele frequency in healthy populations
- Claim: A brand-new, never-reported IRF6 variant should be classified as ____ (benign / pathogenic / VUS) at this moment.
- Evidence: The database shows ____ about how often it appears and what conditions it is linked to.
- Reasoning: Therefore the call is ____, because a classification depends on the weight of evidence and can change as more is gathered.
How this is graded (rubric)
For: Given a patient's IRF6 change reported in no database, write the call you would record right now using the three categories and name the one piece of evidence you would most want next to move it off uncertain.
| Criterion | Proficient | Developing | Beginning |
|---|---|---|---|
| Complete | Every required part of the artifact is present and filled in. | Most parts are present, but one is missing or left blank. | Several parts are missing. |
| Accurate | The science and data are correct and match the evidence. | Mostly correct, with a small factual slip. | Key science or data is wrong. |
| Scientific reasoning (CER) | States a claim, backs it with specific evidence, and explains the reasoning. | Has a claim and evidence, but the reasoning is thin or missing. | Gives an answer with no evidence or reasoning. |
| Professional communication | Clear, organized, and labeled the way a clinician or scientist would write it. | Readable but disorganized or missing labels. | Hard to follow. |
| Submitted | Turned in through the route named under Submit here and confirmed. | Turned in, but in the wrong place or unconfirmed. | Not turned in. |
How the model answer scores against this rubric
- CompleteProficient: Nothing is left blank: the model fills every part of "Given a patient's IRF6 change reported in no database, write the call you would record right now using the three categories and name the one piece of evidence you would most want next to move it off uncertain.".
- AccurateProficient: Every number and claim matches the case evidence.
- Scientific reasoning (CER)Proficient: It names a claim, cites the specific evidence, and explains the reasoning, not just the answer.
- Professional communicationProficient: It is organized and labeled like a real chart note.
- SubmittedProficient: It would be attached to your class form or handed in, and confirmed.
What's next: When we read variants we saw codes like R84C and R250X. What kinds of typos in DNA do those codes actually stand for?