ClinVar Genomic variation as it relates to human health
NM_138711.6(PPARG):c.362A>G (p.Tyr121Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_138711.6(PPARG):c.362A>G (p.Tyr121Cys)
Variation ID: 1070305 Accession: VCV001070305.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.2 3: 12381463 (GRCh38) [ NCBI UCSC ] 3: 12422962 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 10, 2021 Apr 20, 2024 Sep 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_138711.6:c.362A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_619725.3:p.Tyr121Cys missense NM_001330615.4:c.362A>G NP_001317544.2:p.Tyr121Cys missense NM_001354666.3:c.362A>G NP_001341595.2:p.Tyr121Cys missense NM_001354667.3:c.362A>G NP_001341596.2:p.Tyr121Cys missense NM_001354668.2:c.452A>G NP_001341597.1:p.Tyr151Cys missense NM_001354669.2:c.-66A>G 5 prime UTR NM_001354670.2:c.368A>G NP_001341599.1:p.Tyr123Cys missense NM_001374261.3:c.362A>G NP_001361190.2:p.Tyr121Cys missense NM_001374262.3:c.362A>G NP_001361191.2:p.Tyr121Cys missense NM_001374263.2:c.362A>G NP_001361192.2:p.Tyr121Cys missense NM_001374264.2:c.362A>G NP_001361193.2:p.Tyr121Cys missense NM_001374265.1:c.452A>G NP_001361194.1:p.Tyr151Cys missense NM_001374266.1:c.368A>G NP_001361195.1:p.Tyr123Cys missense NM_005037.7:c.362A>G NP_005028.5:p.Tyr121Cys missense NM_015869.5:c.452A>G NP_056953.2:p.Tyr151Cys missense NM_138712.5:c.362A>G NP_619726.3:p.Tyr121Cys missense NC_000003.12:g.12381463A>G NC_000003.11:g.12422962A>G NG_011749.1:g.98614A>G - Protein change
- Y121C, Y123C, Y151C
- Other names
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- Canonical SPDI
- NC_000003.12:12381462:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PPARG | - | - |
GRCh38 GRCh37 |
202 | 262 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2022 | RCV001382404.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 22, 2022 | RCV003227971.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 6, 2023 | RCV004017828.1 | |
PPARG-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Apr 30, 2023 | RCV004528495.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001581157.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tyrosine with cysteine at codon 151 of the PPARG protein (p.Tyr151Cys). The tyrosine residue is highly conserved and there is a … (more)
This sequence change replaces tyrosine with cysteine at codon 151 of the PPARG protein (p.Tyr151Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects PPARG protein function (PMID: 21479595). This variant has been observed in individual(s) with familial partial lipodystrophy (PMID: 21479595, 28641778). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). (less)
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Likely pathogenic
(Jan 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001765776.3
First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate loss-of-function with reduced DNA binding and reduced transcriptional activity (Visser et al., 2011; Majithia et al., 2014); In silico analysis supports … (more)
Published functional studies demonstrate loss-of-function with reduced DNA binding and reduced transcriptional activity (Visser et al., 2011; Majithia et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25157153, 21479595, 28641778, 32041611, 34670072, 33832869) (less)
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Pathogenic
(Apr 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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PPARG-related familial partial lipodystrophy
Type 2 diabetes mellitus
Affected status: yes, unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV003925165.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
The c.362A>G variant identified in PPARG has previously been reported in the literature in individuals with familial partial lipodystrophy (FPLD) [PMIDs: 21479595, 28641778, 32041611, 33502018], … (more)
The c.362A>G variant identified in PPARG has previously been reported in the literature in individuals with familial partial lipodystrophy (FPLD) [PMIDs: 21479595, 28641778, 32041611, 33502018], and it has also been deposited in ClinVar as pathogenic/likely pathogenic [Variation ID: 1070305]. This variant is observed at a very low frequency (~0.002% alternate allele frequency) across the population databases (gnomAD v2.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The predicted p.(Tyr121Cys) variant (also reported as p.(Tyr151Cys)) replaces an evolutionarily conserved tyrosine amino acid with cysteine in the DNA binding domain of the encoded protein [PMIDs: 25154720, 21479595]. In vitro studies on this variant demonstrated reduced DNA-binding capacity and transcriptional activity affecting PPARG function [PMID: 21479595]. In silico predictions are also in favor of deleterious effect of the c.362A>G variant on the encoded transcript [CADD v1.6= 28.7, REVEL= 0.979]. Based on available evidence, this heterozygous c.362A>G (p.(Tyr121Cys)) variant identified in PPARG is reported as Pathogenic. (less)
Observation 1:
Clinical Features:
Hypertriglyceridemia (present) , Hepatic steatosis (present) , Type 2 diabetes mellitus (present)
Secondary finding: no
Observation 2:
Clinical Features:
Hyperlipidemia (present)
Secondary finding: no
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Likely pathogenic
(Apr 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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PPARG-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004108449.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PPARG c.452A>G variant is predicted to result in the amino acid substitution p.Tyr151Cys. This variant has been reported in the heterozygous state in a … (more)
The PPARG c.452A>G variant is predicted to result in the amino acid substitution p.Tyr151Cys. This variant has been reported in the heterozygous state in a family with non-obese type 2 diabetes and partial lipodystrophy (Figure 1. Visser et al. 2011. PubMed ID: 21479595). This variant has also been reported in multiple individuals with partial lipodystrophy (Table S2 - Eldin et al. 2021. PubMed ID: 33502018). This variant was also reported in a large cohort study of patients tested for dyslipidemias (Table S3 - Dron et al. 2020. PubMed ID: 32041611). Functional studies suggest that the p.Tyr151Cys variant led to impaired DNA-binding and reduced transcriptional activity (Visser et al. 2011. PubMed ID: 21479595; Majithia et al. 2014. PubMed ID: 25157153). This variant is present in 2 out of 31,388 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/3-12422962-A-G). This variant is interpreted as likely pathogenic. (less)
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Likely Pathogenic
(Sep 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial partial lipodystrophy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847317.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Tyr121Cys (also known as p.Tyr151Cys) variant in PPARG has been reported in at least 8 individuals with familial partial lipodystrophy and segregated with disease … (more)
The p.Tyr121Cys (also known as p.Tyr151Cys) variant in PPARG has been reported in at least 8 individuals with familial partial lipodystrophy and segregated with disease in at least 5 affected individuals from 2 families (Akinci 2017 PMID: 28641778, Eldin 2021 PMID: 33502018, Gutierrez Alvarez 2021 PMID: 34991302, Vasandani 2022 PMID: 36397776, Visser 2011 PMID: 21479595). It has also been identified in 0.013% (2/15272) Latino/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 1070305). In vitro functional studies provide some evidence that this variant impacts protein function (Visser 2011 PMID: 21479595); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses also support that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial partial lipodystrophy. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PP3, PS3_Supporting. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Phenotypic Differences Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants. | Vasandani C | Journal of the Endocrine Society | 2022 | PMID: 36397776 |
Genotype - phenotype correlation in an adolescent girl with pathogenic PPARy genetic variation that caused severe hypertriglyceridemia and early onset type 2 diabetes. | Gutierrez Alvarez A | Annals of pediatric endocrinology & metabolism | 2021 | PMID: 34991302 |
Cardiac phenotype in familial partial lipodystrophy. | Eldin AJ | Clinical endocrinology | 2021 | PMID: 33502018 |
Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. | Dron JS | BMC medical genomics | 2020 | PMID: 32041611 |
Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial lipodystrophy. | Akinci B | Metabolism: clinical and experimental | 2017 | PMID: 28641778 |
Characterisation of non-obese diabetic patients with marked insulin resistance identifies a novel familial partial lipodystrophy-associated PPARγ mutation (Y151C). | Visser ME | Diabetologia | 2011 | PMID: 21479595 |
Text-mined citations for rs1354592503 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.