About PPARG
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PPARG c.922C>T, p.(Arg308Cys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is present at extremely low frequency in population databases. gnomAD v2.1 reports an allele frequency of 0.00040% (1/250,872 alleles) and gnomAD v4.1 reports 0.00056% (9/1,614,096 alleles), both well below the PM2 threshold of <0.1%. No homozygotes have been observed.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no significant impact on the gene product. REVEL score is 0.441, below the 0.5 threshold for damaging prediction. BayesDel score is 0.204, below the 0.27 threshold. SpliceAI predicts no splicing impact (max delta 0.00).
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
9 / 1,614,096 alleles
gnomAD v4.1: 9 / 1,614,096 alleles. Recorded AF 5.57588e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.9861e-06; MAF= 0.00040%, 1/250872 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.44188e-05; MAF= 0.00544%, 1/18376 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PPARG, a nuclear receptor, is known to behave as an oncoprotein when fused with with PAX8 in thyroid cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55140987, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 13 not met · 9 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_015869.4:c.922C>T (p.Arg308Cys) in PPARG is a missense variant present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00040%, v4.1 AF=0.00056%), meeting PM2 (moderate).
Multiple in silico predictors (REVEL 0.441, BayesDel 0.204, SpliceAI max delta 0.00) suggest no significant deleterious impact, meeting BP4 (supporting benign).
No variant-specific functional evidence was identified. A saturation mutagenesis study of all PPARG missense variants (PMID:27749844) tested this variant in pooled assays but did not individually report functional data for p.Arg308Cys in the published manuscript. The nearby substitution p.Arg308Pro was classified as benign.
This variant has been reported in ClinVar as uncertain significance by a single submitter (SCV001337589, Personalized Diabetes Medicine Program) in association with monogenic diabetes. No pathogenic or benign assertion has been made by an expert panel.
Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868), one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) do not meet the threshold for likely pathogenic (requires ≥2 moderate or 1 moderate + ≥4 supporting) or likely benign (requires ≥2 supporting benign). The variant is classified as uncertain significance (VUS).
No criteria match.
Met · 2
PM2 ModerateThis variant is present at extremely low frequency in population databases. gnomAD v2.1 reports an allele frequency of 0.00040% (1/250,872 alleles) and gnomAD v4.1 reports 0.00056% (9/1,614,096 alleles), both well below the PM2 threshold of <0.1%. No homozygotes have been observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=3.99e-06 (1/250
- 872)
- 0 homozygotes
- gnomAD v4.1: AF=5.58e-06 (9/1
- 614
- 096)
- grpmax FAF=2.92e-06
- Highest subpopulation AF: East Asian
- 0.00544% (v2.1)
- 0.00223% (v4.1)
Sources
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. REVEL score is 0.441, below the 0.5 threshold for damaging prediction. BayesDel score is 0.204, below the 0.27 threshold. SpliceAI predicts no splicing impact (max delta 0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.441 (below 0.5 damaging threshold)
- BayesDel: 0.204 (below 0.27 damaging threshold)
- SpliceAI: max delta 0.00 (no predicted splice impact)
Sources
Not met · 13 · evaluated, threshold not reached
PS1 No known pathogenic variant with the same amino acid change (p.Arg308Cys) has been reported. ClinVar lists this variant as uncertain significance from a single submitter. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- no pathogenic assertion at this residue
Sources
PS3 No variant-specific functional evidence demonstrating a damaging effect on the gene or gene product was identified. The saturation mutagenesis study (PMID:27749844) tested this variant in pooled assays but did not individually report or discuss p.Arg308Cys in the published text or accessible supplementary data. OncoKB reports unknown oncogenic effect. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- PMID:27749844 saturation mutagenesis did not individually name this variant
Still missing
- Supplementary data from PMID:27749844 may contain functional scores for R308C but are not available in full text
Sources
PM1 Although residue 308 lies within the PPARγ ligand-binding domain, it is not in a statistically significant mutational hotspot. The amino acid position tolerates at least some substitutions; p.Arg308Pro was classified as benign (PMID:27749844). Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue not significant
- PMID:27749844 reports p.R308P as benign
PM5 No pathogenic missense variant at the same amino acid residue (Arg308) was identified. Automated PM5 candidate harvesting found no same-residue pathogenic comparators in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates
- 0 expert-panel P/LP candidates
Sources
pm5_candidates
PP2 While PPARG missense variants are a known mechanism for FPLD3, PPARG does not have a low rate of benign missense variation. Approximately 80% of rare PPARG missense variants are functionally neutral (PMID:27749844), indicating the gene tolerates substantial benign missense variation. Details ▾Hide ▴
Evidence considered
- PMID:27749844: ~80% of rare PPARG missense variants are functionally neutral
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.441 (below 0.5 threshold), BayesDel score is 0.204 (below 0.27 damaging threshold), and SpliceAI predicts no splice impact (max delta 0.00). HCI prior is not available for PPARG. Details ▾Hide ▴
Evidence considered
- REVEL: 0.441 (below damaging threshold of 0.5)
- BayesDel: 0.204 (below damaging threshold of ~0.27)
- SpliceAI: max delta 0.00
Sources
PP5 No reputable source reports this variant as pathogenic. The ClinVar entry is classified as uncertain significance by a single submitter. Details ▾Hide ▴
BA1 The allele frequency in gnomAD (0.00040–0.00056%) is far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- gnomAD AF: 0.00040–0.00056%
- well below 1% BA1 threshold
Sources
BS1 The allele frequency in gnomAD (0.00040–0.00056%; highest subpopulation 0.00544% East Asian v2.1) is far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Highest subpopulation AF: 0.00544% (East Asian
- v2.1)
- well below 0.3% BS1 threshold
Sources
BS3 No variant-specific functional studies demonstrating no damaging effect on the gene product were identified. The saturation mutagenesis study (PMID:27749844) tested this variant but did not individually report the functional score for p.Arg308Cys in the published text. Details ▾Hide ▴
Evidence considered
- No variant-specific benign functional data available
Still missing
- Supplementary data from PMID:27749844 may contain functional scores but are not accessible
BP1 PPARG-related familial partial lipodystrophy type 3 is primarily caused by missense variants, not truncating variants. BP1 is not applicable when the disease mechanism is predominantly missense-mediated. Details ▾Hide ▴
Evidence considered
- FPLD3 is a missense-driven disorder (PMID:27749844)
- PPARG frameshift mutations also reported (PMID:39017680)
BP6 No reputable source reports this variant as benign. The ClinVar classification is uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- no benign assertion from any submitter
Sources
PS5 No reputable source reports this variant as pathogenic. ClinVar classification is uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- criteria provided
- single submitter
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo data (with confirmed maternity and paternity) are available for this variant. Details ▾Hide ▴
Still missing
- No de novo observation reported
PS4 Insufficient case-control data available. A single ClinVar submission reports this variant in a monogenic diabetes context, but no prevalence comparison against controls has been published. Details ▾Hide ▴
Evidence considered
- Single ClinVar submission (SCV001337589) in monogenic diabetes context
- insufficient for case-control analysis
Still missing
- No published case-control study for this variant
Sources
PM6 No de novo observation (without confirmation of maternity/paternity) has been reported for this variant. Details ▾Hide ▴
Still missing
- No de novo data available
PP1 No cosegregation data in affected family members are available for this variant. Details ▾Hide ▴
Still missing
- No family segregation studies available
PP4 No patient-specific phenotype or family history data are available. The single ClinVar submission associates the variant with monogenic diabetes, but detailed clinical information is not provided. Details ▾Hide ▴
Evidence considered
- ClinVar SCV001337589: Monogenic diabetes
- no detailed phenotype
Still missing
- No detailed patient phenotype data available
Sources
BS2 The variant has been observed in gnomAD (1 heterozygous carrier in v2.1, 9 in v4.1), but the phenotype of these carriers is unknown. Without documented observation in healthy adults, BS2 cannot be assessed. Details ▾Hide ▴
Evidence considered
- gnomAD carriers identified but without phenotype data
- FPLD3 may have variable expressivity and late onset
Still missing
- Phenotype of gnomAD carriers unknown
Sources
BS4 No segregation data in affected family members are available to assess lack of segregation. Details ▾Hide ▴
Still missing
- No family segregation data available
BP2 No phasing data (in trans or in cis with another pathogenic variant) are available for this variant. Details ▾Hide ▴
Still missing
- No phasing data available
BP5 No data available demonstrating this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_015869.4:c.922C>T is a missense variant (p.Arg308Cys), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). PVS1 is not applicable to missense substitutions per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution
- variant_bucket=other
- apply_generic_pvs1_framework=false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ASkipped per instructions. PM3 requires observation in trans with a pathogenic variant; no phasing data available and not part of the assess list for this case. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per instructions. PM4 applies to in-frame deletions/insertions or stop-loss variants; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ASkipped per instructions. BP3 applies to in-frame indels in repeat regions; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_015869.4:c.922C>T is a missense variant (p.Arg308Cys), not synonymous. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PPARG
- Transcript
- NM_015869.4
- Coding (HGVS c.)
- NM_015869.4:c.922C>T
- Protein (HGVS p.)
- NP_056953.2:p.(Arg308Cys)
- GRCh38
- chr3:12416806 C>T
- GRCh37
- chr3:12458305 C>T
- ClinVar
- 917446
- COSMIC
- COSV55140987
Gene diagram
Every interpreted variant in PPARG, mapped onto the exon structure of NM_015869.4. Select a row to find it on the plot.
PPARGNM_015869.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PPARG
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
9 / 1,614,096 alleles
AF 5.58e-06 · 0 homozygotes · FAF 2.92e-06
gnomAD v2.1
1 / 250,872 alleles
AF 3.99e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5.6e-06 · 9 / 1,614,096 alleles · 0 hom · FAF 2.9e-06
| East Asian1 / 44,874 | 2.2e-05 |
| European (non-Finnish)8 / 1,179,976 | 6.8e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 250,872 alleles · 0 hom
| East Asian1 / 18,376 | 5.4e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.57588e-06; MAF= 0.00056%, 9/1614096 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22846e-05; MAF= 0.00223%, 1/44874 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.9861e-06; MAF= 0.00040%, 1/250872 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.44188e-05; MAF= 0.00544%, 1/18376 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.441
- BayesDel
- 0.204
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. REVEL score is 0.441, below the 0.5 threshold for damaging prediction. BayesDel score is 0.204, below the 0.27 threshold. SpliceAI predicts no splicing impact (max delta 0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.441 (below 0.5 damaging threshold)
- BayesDel: 0.204 (below 0.27 damaging threshold)
- SpliceAI: max delta 0.00 (no predicted splice impact)
Sources
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.441 (below 0.5 threshold), BayesDel score is 0.204 (below 0.27 damaging threshold), and SpliceAI predicts no splice impact (max delta 0.00). HCI prior is not available for PPARG. Details ▾Hide ▴
Evidence considered
- REVEL: 0.441 (below damaging threshold of 0.5)
- BayesDel: 0.204 (below damaging threshold of ~0.27)
- SpliceAI: max delta 0.00
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_015869.4:c.922C>T is a missense variant (p.Arg308Cys), not synonymous. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.441. BayesDel score = 0.204196.
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015This is the ACMG/AMP standards and guidelines paper for sequence variant interpretation. It describes the generic classification framework and criteria definitions but contains no variant-specific data for NM_015869.4:c.922C>T or any PPARG variant.Does not name this variant
-
PMID 27749844 ↗Prospective functional classification of all possible missense variants in PPARG.Majithia AR et al. · 2016This saturation mutagenesis study characterized all 9,595 possible missense variants in PPARG using a pooled CD36 reporter assay in human macrophages. The variant p.Arg308Cys (R308C) was included in the experimental library but is not individually named or discussed in the manuscript. The adjacent substitution p.Arg308Pro (R308P) at the same residue was classified as benign based on integrated function score and clinical phenotype.Does not name this variant
Quoted passage
Three variants (p.M31L, p.R308P, p.R385Q) classified as benign with high confidence were found in individuals with clinical features of partial lipodystrophy.
Results, body text — R308P mentioned in paragraph describing benign variants
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
9 / 1,614,096 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/917446/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-12458305-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-12416806-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-12416806-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_015869.4%3Ac.922C…
- OncoKB ↗www.oncokb.org/gene/PPARG/R308C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123039271
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.57588e-06; MAF= 0.00056%, 9/1614096 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22846e-05; MAF= 0.00223%, 1/44874 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.9861e-06; MAF= 0.00040%, 1/250872 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.44188e-05; MAF= 0.00544%, 1/18376 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 917446)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.441. BayesDel score = 0.204196.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PPARG, a nuclear receptor, is known to behave as an oncoprotein when fused with with PAX8 in thyroid cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55140987, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.