3-12434111-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. 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 (★★).

• 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• 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.
• 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 [Likely_pathogenic]. Clinvar id is 8136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPARG	NM_138711.6	c.1394C>T	p.Pro465Leu	missense_variant	Exon 8 of 8	ENST00000651735.1	NP_619725.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPARG	ENST00000651735.1	c.1394C>T	p.Pro465Leu	missense_variant	Exon 8 of 8		NM_138711.6	ENSP00000498313.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251034 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135766

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PPARG-related familial partial lipodystrophy Pathogenic:2

Apr 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PPARG c.1484C>T (p.Pro495Leu) variant, also known as p.Pro467Leu, is reported in a study by Barroso et al. (1999) in which it is found in a heterozygous state in one individual with familial partial lipodystrophy and her affected son. The variant was not found in any of the five unaffected family members tested, showing that the variant segregated with disease over two generations. The p.Pro495Leu variant was absent from 314 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The p.Pro495Leu variant is located in the PPARG ligand binding domain. 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. Mice who were heterozygous for the variant showed abnormal fat distribution and hypertension but not insulin resistance. Based on the evidence the p.Pro495Leu variant is classified as likely pathogenic for familial partial lipodystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Lipodystrophy Pathogenic:1

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Pro495Leu variant (sometimes called p.Pro467Leu) in PPARG has been reported in 2 individuals with lipodystrophy, segregated with disease in these 2 affected relatives from 1 family (PMID: 10622252), and has been identified in 0.0009% (1/113420) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121909244). This variant has also been reported in ClinVar as a VUS, likely pathogenic, and pathogenic (Variation ID: 8136). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that the p.Pro495Leu variant may impact protein function (PMID: 10622252). However, these types of assays may not accurately represent biological function. Animal models in mice have shown that this variant causes lipodystrophy (PMID: 15254591). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant was found to be de novo in 1 individual with confirmed paternity and maternity (PMID: 10622252). The p.Pro495Leu is located in a region of PPARG that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 10622252). In summary, this variant meets criteria to be classified as pathogenic for lipodystrophy in an autosomal dominant manner based on a mouse model for this variant having the same phenotype as well as a de novo occurrence of this variant in an affected patient. ACMG/AMP Criteria applied: PS2, PS3, PM2, PM1, PP3 (Richards 2015). -

not provided Pathogenic:1

Nov 18, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with leucine at codon 495 of the PPARG protein (p.Pro495Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial partial lipodystrophy type 3 (PMID: 12663460, 10622252). In at least one individual the variant was observed to be de novo. This variant is also known as p.Pro467Leu in the literature. ClinVar contains an entry for this variant (Variation ID: 8136). Experimental studies have shown that this variant affects PPARG protein function (PMID: 10622252, 12663460, 22539598, 15254591, 17003330). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Benign	0.63	D
LIST_S2	Pathogenic	1.0	.;.;.;.;.;.;D;.;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.7	.;.;.;.;.;.;.;.;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.3	D;D;D;.;.;.;D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;.;.;.;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;.;.;.;D;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909244; hg19: chr3-12475610;