NM_015869.4:c.922C>T

PPARG · NP_056953.2:p.(Arg308Cys) · NM_015869.4

GRCh37: chr3:12458305 C>T · GRCh38: chr3:12416806 C>T

Gene: PPARG Transcript: NM_015869.4

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

PPARG

Transcript

NM_015869.4

Protein

NP_056953.2:p.(Arg308Cys)

gnomAD AF

5.575876527790169e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	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.	clinvar
PS2	Not assessed	No de novo data (with confirmed maternity and paternity) are available for this variant.
PS3	Not met	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.	oncokb
PS4	Not assessed	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.	clinvar
PS5	Not met	No reputable source reports this variant as pathogenic. ClinVar classification is uncertain significance.	clinvar
PM3	N/A	Skipped 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.
PM4	N/A	Skipped per instructions. PM4 applies to in-frame deletions/insertions or stop-loss variants; this is a missense substitution.
PM1	Not met	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).
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Not met	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.	pm5_candidates
PM6	Not assessed	No de novo observation (without confirmation of maternity/paternity) has been reported for this variant.
PP1	Not assessed	No cosegregation data in affected family members are available for this variant.
PP2	Not met	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	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.	clinvar
PP5	Not met	No reputable source reports this variant as pathogenic. The ClinVar entry is classified as uncertain significance by a single submitter.	clinvar
BA1	Not met	The allele frequency in gnomAD (0.00040–0.00056%) is far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	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%.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.
BS4	Not assessed	No segregation data in affected family members are available to assess lack of segregation.
BP1	Not met	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.
BP2	Not assessed	No phasing data (in trans or in cis with another pathogenic variant) are available for this variant.
BP3	N/A	Skipped per instructions. BP3 applies to in-frame indels in repeat regions; this is a missense substitution.
BP4	Met	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).	revel bayesdel spliceai
BP5	Not assessed	No data available demonstrating this variant in a case with an alternate molecular basis for disease.
BP6	Not met	No reputable source reports this variant as benign. The ClinVar classification is uncertain significance.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_015869.4:c.922C>T is a missense variant (p.Arg308Cys), not synonymous.

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