rs121909244

Variant names:

• chr3-12434111-C-T
• rs121909244
• NM_138711.6:c.1394C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-12434111-C-T
• chr3-12434111-C-A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_138711.6(PPARG):​c.1394C>T​(p.Pro465Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000440531: Functional studies showed that the variant protein had severely impaired ligand binding ability, abnormal activation profile and inhibited the function of the wild type protein (Barroso et al. 1999). Majithia et al. (2014) describe an in vitro assay wherein the p.Pro495Leu variant had a significantly reduced ability to rescue differentiation of adipocytes when compared to wild type PPARG. Modrick et al. (2012) showed that mice with the p.Pro495Leu variant had vascular dysfunction not seen in the wild type mice. Tsai et al. (2004) demonstrated that homozygosity for the variant is lethal in utero for mice establishing that the mutant protein is functionally null." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PPARG NM_138711.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.86
• Publications: 109 publications found

Genes affected

PPARG (HGNC:9236): (peroxisome proliferator activated receptor gamma) This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) and these heterodimers regulate transcription of various genes. Three subtypes of PPARs are known: PPAR-alpha, PPAR-delta, and PPAR-gamma. The protein encoded by this gene is PPAR-gamma and is a regulator of adipocyte differentiation. Additionally, PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Jul 2008]

PPARG Gene-Disease associations (from GenCC):

• PPARG-related familial partial lipodystrophy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• lipodystrophy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Berardinelli-Seip congenital lipodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000440531: Functional studies showed that the variant protein had severely impaired ligand binding ability, abnormal activation profile and inhibited the function of the wild type protein (Barroso et al. 1999). Majithia et al. (2014) describe an in vitro assay wherein the p.Pro495Leu variant had a significantly reduced ability to rescue differentiation of adipocytes when compared to wild type PPARG. Modrick et al. (2012) showed that mice with the p.Pro495Leu variant had vascular dysfunction not seen in the wild type mice. Tsai et al. (2004) demonstrated that homozygosity for the variant is lethal in utero for mice establishing that the mutant protein is functionally null.; SCV001422819: "In vitro functional studies provide some evidence that the p.Pro495Leu variant may impact protein function (PMID: 10622252)."; SCV002245817: Experimental studies have shown that this variant affects PPARG protein function (PMID: 10622252, 12663460, 22539598, 15254591, 17003330).
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PPARG gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.1192 (below the threshold of 3.09). Trascript score misZ: 3.0978 (above the threshold of 3.09). GenCC associations: The gene is linked to PPARG-related familial partial lipodystrophy, Berardinelli-Seip congenital lipodystrophy, lipodystrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 3-12434111-C-T is Pathogenic according to our data. Variant chr3-12434111-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138711.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	NM_138711.6	MANE Select	c.1394C>T	p.Pro465Leu	missense	Exon 8 of 8	NP_619725.3	E9PFV2
	PPARG	NM_015869.5		c.1484C>T	p.Pro495Leu	missense	Exon 7 of 7	NP_056953.2
	PPARG	NM_001354666.3		c.1394C>T	p.Pro465Leu	missense	Exon 8 of 8	NP_001341595.2	E9PFV2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPARG	ENST00000651735.1	MANE Select	c.1394C>T	p.Pro465Leu	missense	Exon 8 of 8	ENSP00000498313.1	E9PFV2
	PPARG	ENST00000287820.10	TSL:1	c.1484C>T	p.Pro495Leu	missense	Exon 7 of 7	ENSP00000287820.6	P37231-1
	PPARG	ENST00000397010.7	TSL:1	c.1394C>T	p.Pro465Leu	missense	Exon 8 of 8	ENSP00000380205.3	E9PFV2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251034 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000263 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	PPARG-related familial partial lipodystrophy (2)
1	-	-	Lipodystrophy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Benign	0.63	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.86		Gain of stability (P = 0.0129)
MVP		0.96
MPC		2.1
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.84
gMVP		0.68
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121909244; hg19: chr3-12475610;