NM_138711.6(PPARG):c.491G>A (p.Arg164Gln) AND PPARG-related familial partial lipodystrophy

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 22, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000499572.9

Allele description [Variation Report for NM_138711.6(PPARG):c.491G>A (p.Arg164Gln)]

NM_138711.6(PPARG):c.491G>A (p.Arg164Gln)

Gene:

PPARG:peroxisome proliferator activated receptor gamma [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.2

Genomic location:

Preferred name:

NM_138711.6(PPARG):c.491G>A (p.Arg164Gln)

HGVS:

NC_000003.12:g.12392714G>A
NG_011749.1:g.109865G>A
NM_001330615.4:c.491G>A
NM_001354666.3:c.491G>A
NM_001354667.3:c.491G>A
NM_001354668.2:c.581G>A
NM_001354669.2:c.64G>A
NM_001354670.2:c.497G>A
NM_001374261.3:c.491G>A
NM_001374262.3:c.491G>A
NM_001374263.2:c.491G>A
NM_001374264.2:c.491G>A
NM_001374265.1:c.581G>A
NM_001374266.1:c.497G>A
NM_005037.7:c.491G>A
NM_015869.5:c.581G>A
NM_138711.6:c.491G>AMANE SELECT
NM_138712.5:c.491G>A
NP_001317544.2:p.Arg164Gln
NP_001341595.2:p.Arg164Gln
NP_001341596.2:p.Arg164Gln
NP_001341597.1:p.Arg194Gln
NP_001341598.1:p.Gly22Ser
NP_001341599.1:p.Arg166Gln
NP_001361190.2:p.Arg164Gln
NP_001361191.2:p.Arg164Gln
NP_001361192.2:p.Arg164Gln
NP_001361193.2:p.Arg164Gln
NP_001361194.1:p.Arg194Gln
NP_001361195.1:p.Arg166Gln
NP_005028.5:p.Arg164Gln
NP_056953.2:p.Arg194Gln
NP_056953.2:p.Arg194Gln
NP_619725.3:p.Arg164Gln
NP_619726.3:p.Arg164Gln
NC_000003.11:g.12434213G>A
NM_015869.4(PPARG):c.581G>A
NM_015869.4:c.581G>A
p.Arg194Gln

Protein change:

G22S

Links:

dbSNP: rs148195788

NCBI 1000 Genomes Browser:

rs148195788

Molecular consequence:

NM_001330615.4:c.491G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354666.3:c.491G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354667.3:c.491G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354668.2:c.581G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354669.2:c.64G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354670.2:c.497G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374261.3:c.491G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374262.3:c.491G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374263.2:c.491G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374264.2:c.491G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374265.1:c.581G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374266.1:c.497G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005037.7:c.491G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_015869.5:c.581G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_138711.6:c.491G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_138712.5:c.491G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: PPARG-related familial partial lipodystrophy
Synonyms:: LIPODYSTROPHY, FAMILIAL PARTIAL, ASSOCIATED WITH PPARG MUTATIONS; Familial partial lipodystrophy 3
Identifiers:: MONDO: MONDO:0011448; MedGen: C1720861; Orphanet: 79083; OMIM: 604367

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000596559	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 8, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001423110	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000596559

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 8, 2016)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001423110

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 22, 2020)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000596559.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001423110.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The p.Arg194Gln variant in PPARG has been reported in 2 individuals suspected to have Familial Partial Lipodystrophy (PMID: 27749844), and has also been reported likely pathogenic in ClinVar (Variation ID: 436397). This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg194Gln variant may eliminate protein function (PMID: 27749844). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant, causing a different amino acid change at the same position, p.Arg194Trp, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 17299075; DOI: 10.1530/endoabs.41.GP59). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3, PM5_Supporting (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 30, 2024

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