NM_015869.4:c.338C>T

PPARG · NP_056953.2:p.(Pro113Leu) · NM_015869.4

GRCh37: chr3:12422848 C>T · GRCh38: chr3:12381349 C>T

Gene: PPARG Transcript: NM_015869.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

PPARG

Transcript

NM_015869.4

Protein

NP_056953.2:p.(Pro113Leu)

gnomAD AF

1.2398149204286784e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_015869.4:c.338C>T (p.Pro113Leu) in PPARG is a missense variant absent from ClinVar and present at an extremely low allele frequency of 1.24×10⁻⁶ (2/1,613,144 alleles, 0 homozygotes) in gnomAD v4.1, meeting PM2 at supporting strength (well below 0.1% threshold).

REVEL in silico prediction yields a score of 0.74, exceeding the 0.5 threshold for a deleterious call, meeting PP3 at supporting strength. SpliceAI predicts no splicing impact (max delta score 0.00) and BayesDel (0.293) is borderline.

No functional studies, de novo reports, segregation data, or disease-specific cohort data were identified for this variant. PVS1 is not applicable as this is a missense variant (ClinGen SVI PVS1 framework, PMC6185798). All remaining assessed pathogenic and benign criteria were not met.

With only PM2 (supporting) and PP3 (supporting) met, the evidence is insufficient to reach a Likely Pathogenic or Likely Benign classification under generic ACMG/AMP 2015 combination rules (PMID:25741868). This variant is classified as a Variant of 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.338C>T is a missense variant (p.Pro113Leu); it does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework
PS1	Not met	No prior report of the same amino acid change (p.Pro113Leu) as a pathogenic variant exists in ClinVar or the literature; this variant is absent from all ClinVar records.	clinvar
PS2	Not met	No de novo occurrence data are available for this variant in any database or published literature.	clinvar
PS3	Not assessed	No well-established in vitro or in vivo functional studies were identified for NM_015869.4:c.338C>T (p.Pro113Leu). OncoKB assigns 'Unknown Oncogenic Effect' and provides no variant-specific functional evidence.	oncokb
PS4	Not met	No case-control or cohort data are available to assess whether the prevalence of this variant is significantly increased in affected individuals; the variant is absent from ClinVar.	clinvar gnomad_v4
PS5	Not met	No same-residue different amino acid change (PM5-style comparator) has been established as pathogenic in ClinVar or the literature. PM5 candidate harvesting found no eligible comparators.	pm5_candidates clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org. Domain-level assessment for a critical functional domain was not performed due to lack of domain annotation in the evidence packet.
PM2	Met	NM_015869.4:c.338C>T is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and present at an allele frequency of 1.24×10⁻⁶ (0.00012%, 2/1,613,144 alleles) in gnomAD v4.1 with no homozygotes. This frequency is well below the 0.1% threshold for PM2.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Unable to confirm classic same-residue PM5 semantics; PM5 candidate harvesting found no eligible pathogenic comparator variants at residue 113.	pm5_candidates
PM6	Not met	No assumed or confirmed de novo occurrence has been reported for this variant.	clinvar
PP1	Not met	No cosegregation data are available for this variant; no family studies have been reported.
PP2	Not met	PPARG missense constraint metrics are not available in the evidence packet (HCI prior score not available for PPARG). Without evidence of a low rate of benign missense variation, PP2 cannot be applied.
PP3	Met	REVEL in silico predictor assigns a score of 0.74, which is above the commonly accepted threshold for deleterious prediction (>0.5). BayesDel score of 0.293 is borderline. SpliceAI predicts no splicing impact (max delta=0.00). Taken together, the REVEL score provides a single line of computational evidence supporting a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data were provided for this case; the specificity of the patient's presentation cannot be assessed.
PP5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	The population allele frequency of 1.24×10⁻⁶ (0.00012%) in gnomAD v4.1 is far below the 1% threshold for BA1.	gnomad_v4 gnomad_v2
BS1	Not met	The population allele frequency of 1.24×10⁻⁶ (0.00012%) in gnomAD v4.1 is far below the 0.3% threshold for BS1.	gnomad_v4 gnomad_v2
BS2	Not met	Although 2 alleles are observed in gnomAD v4.1, the phenotype of those individuals is unknown. gnomAD population data alone, without confirmation of healthy adult status in the context of a highly penetrant early-onset disorder, is insufficient to meet BS2.	gnomad_v4
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect were identified for this variant. OncoKB assigns 'Unknown Oncogenic Effect' with no variant-specific functional evidence.	oncokb
BS4	Not met	No segregation data are available to assess lack of segregation in affected family members.
BP1	Not met	PPARG is known to harbor disease-causing missense variants (e.g., familial partial lipodystrophy type 3 is caused by PPARG missense mutations such as p.Arg212Trp). BP1 applies only when truncating variants are the primary disease mechanism, which is not the case for PPARG.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a pathogenic variant has been reported for a fully penetrant dominant disorder.
BP4	Not met	REVEL in silico predictor assigns a score of 0.74, which predicts a deleterious effect. Computational evidence is therefore mixed (REVEL predicts damaging, SpliceAI predicts no splicing impact) and does not provide multiple lines of evidence suggesting no impact on the gene product.	revel bayesdel spliceai
BP5	Not met	No data are available indicating this variant was observed in a case with an alternate molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	NM_015869.4:c.338C>T is a missense variant (p.Pro113Leu), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splicing impact and low nucleotide conservation.
BP3	N/A	Variant is a substitution, not an in-frame deletion or insertion in a repetitive region.
PM3	N/A	No evidence for a recessive disease mechanism or detection in trans with a pathogenic variant.
PM4	N/A	Variant is a substitution, not a protein-length-altering in-frame deletion or insertion.

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