Clue 1: Orient yourself
What are the main parts, stages, or choices in this model?
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
Many people carry small instruction changes and stay healthy. How do scientists decide which changes deserve concern?
Why it matters: ClinVar records can disagree or remain uncertain. Leaving an uncertain result uncertain protects families from a false diagnosis and shows where stronger evidence is still needed.
On your WebXam
You can compare variant records, rank the evidence, and leave an uncertain result uncertain.
For life
To find the cause, change one thing and watch what changes.
Principle: Same look, different cause
Try the everyday version first
Same look, different cause
A library card can label a source trusted, harmless, or uncertain only after several records agree. If the records conflict, the card stays uncertain.
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
What changes while the other parts stay the same?
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 check would separate two explanations that still fit the picture?
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.
- 1What are the main parts, stages, or choices in this model?
- 2What changes while the other parts stay the same?
- 3What check would separate two explanations that still fit the picture?
Tier 1 check
Finish with the everyday model
Explain why conflicting records must stay uncertain instead of being ranked as safe or harmful.
Answer in plain words. You can finish this required check without opening either optional section below.
Ready for the real names? Optional tier 2
Craniofacial Research Track
Session 13Reading the Evidence, DecemberLens: Genetics of Disease
ClinVar: which IRF6 changes cause disease?
Discovery question
Many people carry small instruction changes and stay healthy. How do scientists decide which changes deserve concern?
Same look, different cause. Two tiny instruction changes can look alike on a list but carry very different evidence about health.
Before this page, you should know
- predicts a 's 3D structure and colors each part by confidence (pLDDT), dark blue is very high, orange is low.
- A domain is a distinct functional part of a ; IRF6 has a near its front (N-terminal) end.
If not, review
Today's new idea is only
Same look, different cause. Two tiny instruction changes can look alike on a list but carry very different evidence about health.
Goal: Compare three public change records, sort them by the strength of the evidence, and leave an uncertain result uncertain.
Know by the end
- ClinVar is a public archive of reported genetic variants and what they mean for health.
- A is classified as disease-causing; a has an unknown effect.
- Each ClinVar record lists the variant, the gene, the condition, and the clinical significance.
- Filtering by clinical significance separates the IRF6 changes that cause clefting from the ones that probably do not.
1
Search and filter
Model start: Searching IRF6 in ClinVar returns a long list of reported variants, which I can narrow with the filters on the left.
- Search IRF6 in ClinVar and write how many variants are reported (a rough count is fine).
- Use the Clinical significance filter to show only Pathogenic, then only Uncertain significance.
2
Read one record
Model start: One pathogenic IRF6 variant is linked to and is classified as Pathogenic.
- Open one pathogenic IRF6 variant and write the variant name, the condition it is linked to, and its clinical significance.
- Note whether the record lists a review status (how many sources support it).
3
Build the table
- Make a small table with three IRF6 variants: variant name, condition, and clinical significance.
- Include at least one pathogenic and one uncertain (VUS) so the contrast is clear.
clinvar
- Open ClinVar at https://www.ncbi.nlm.nih.gov/clinvar/?term=IRF6%5Bgene%5D (this searches the gene IRF6). If you start from https://www.ncbi.nlm.nih.gov/clinvar/ instead, type IRF6[gene] into the search box and press Search.
- Look at the result count at the top and note roughly how many IRF6 variants are reported.
- In the Filters panel on the left, open classification (clinical significance) and check Pathogenic to show only disease-causing variants.
- Pick one from the list and click its name to open the full record.
- On the record page, write down the variant name, the Gene (IRF6), the Condition(s) it is linked to (for example ), and the classification (Pathogenic).
- Note the Review status (the star rating, showing how many sources agree), then click your browser Back button to return to the list.
- Go back to the Filters and switch the classification to Uncertain significance to find a VUS, and record one of those variants for your table.
Turn in: A small table of three IRF6 variants, each row giving the variant name, the linked condition, and the clinical significance, with at least one Pathogenic and one Uncertain significance (VUS) so the contrast is clear.
ClinVar
Open the tool Lists DNA variants that have been reported, the condition each is linked to, and a clinical-significance call.
When you use this: Use this when you have a specific DNA change and need to know whether anyone has reported it before and whether it was called harmful.
What the screen looks like
Step by step
- 1Open ncbi.nlm.nih.gov/clinvar and search IRF6[gene].
- 2Open one variant from the list (for example R84C).
- 3Read its clinical significance and the review status (how many labs agree).
Capture these fields
- Variant name: R84C (or c.250C>T)
- Condition: Popliteal pterygium syndrome
- Clinical significance: Pathogenic
- VUS vs pathogenic call: Pathogenic, not a VUS, because it recurs in many affected families
How to read it: A pathogenic call means strong evidence the variant causes disease; benign means evidence it does not; a means there is not enough evidence yet. A call can change as more families are reported, so always note the date.
Lost? ClinVar overview NCBI Gene
Open the tool The full reference record for a gene: its official symbol, ID, location, and what it does.
When you use this: Use this first, when you have a gene name and need its official ID and address. It is the home base every other database points back to.
What the screen looks like
Step by step
- 1Go to ncbi.nlm.nih.gov/gene and type the gene symbol IRF6 in the search box, then press Search.
- 2Open the top result whose organism is Homo sapiens (human).
- 3At the top of the record, read three things and write them down: the official symbol, the Gene ID number, and the location ( band).
Capture these fields
- Symbol (official gene name): IRF6
- Gene ID (the stable number): 3664
- Location (chromosome band): 1q32.2
- Summary (one line on its job): A transcription factor needed for the skin-surface cells that let the lip and palate fuse.
How to read it: The symbol and Gene ID let you find the exact same gene in every other database. The location should match the band you mapped (1q32). The summary tells you the gene's job in one sentence.
Lost? NCBI Gene help manual (how to use the Gene database)
Level 1, Guided
Use the sentence starters, a word bank from the vocabulary, a labeled diagram, and the exact source link.
Level 2, Collaborative
Complete a partly blank model or table and explain it.
Level 3, Independent
Make a claim from a new example or an unfamiliar entry in ClinVar.
Team roles
- Manager: keeps the group moving
- Recorder: writes the shared model or table
- Evidence checker: verifies each claim against the source
- Reporter: explains the group's reasoning
Process reflection
- What evidence changed your thinking today?
- What did your group disagree about, and how did you resolve it?
- What question is still unresolved?
By the end of this session, submit ONE of: a labeled diagram with a 2-sentence explanation; a claim, evidence, reasoning paragraph; a completed data table from a real database; or a one-question exit ticket using today's vocabulary.
Recommended here: A small table of three IRF6 variants, each row giving the variant name, the linked condition, and the clinical significance, with at least one Pathogenic and one Uncertain significance (VUS) so the contrast is clear.
Meets standard if your explanation correctly connects structure, timing, gene or protein function, or evidence source to Mateo's case: Compare three public change records, sort them by the strength of the evidence, and leave an uncertain result uncertain.
How this is graded (rubric)
For: A small table of three IRF6 variants, each row giving the variant name, the linked condition, and the clinical significance, with at least one Pathogenic and one Uncertain significance (VUS) so the contrast is clear.
| 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 "A small table of three IRF6 variants, each row giving the variant name, the linked condition, and the clinical significance, with at least one Pathogenic and one Uncertain significance (VUS) so the contrast is clear.".
- 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.
Go deeper Optional tier 3
Everything required is above. Open this section only if you want the research reading and source trail.
Student reading
The idea in plain English
Many people carry small instruction changes and stay healthy. How do scientists decide which changes deserve concern?
A library card can label a source trusted, harmless, or uncertain only after several records agree. If the records conflict, the card stays uncertain.
Same look, different cause. Two tiny instruction changes can look alike on a list but carry very different evidence about health.
- ClinVar is a public archive of reported genetic variants and what they mean for health.
- A is classified as disease-causing; a has an unknown effect.
- Each ClinVar record lists the variant, the gene, the condition, and the clinical significance.
- Filtering by clinical significance separates the IRF6 changes that cause clefting from the ones that probably do not.
This lesson reading is written from the vetted sources in the advanced citation trail below.
Everything you need for today is on this page. These links are optional.
What to read
Read the short plain-language explanation written for this lesson. Plain-language reading for this session
Why this source matters
This explanation gives you the background for today's idea without making you decode a research paper: Same look, different cause. Two tiny instruction changes can look alike on a list but carry very different evidence about health.
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
Stop after the final 'Use it now' section. The research citations are available separately for advanced readers.
Your output
Write one claim-evidence sentence: state the main idea, then name the example or evidence that supports it.
These records and papers document the science. They are not assigned student reading. Use the plain-language lesson reading above unless your teacher asks you to inspect an original source.