7-128254434-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_000230.3(LEP):c.175G>A(p.Gly59Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,670 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 Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

LEP
NM_000230.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.79

Variant links:

Genes affected

LEP (HGNC:6553): (leptin) This gene encodes a protein that is secreted by white adipocytes into the circulation and plays a major role in the regulation of energy homeostasis. Circulating leptin binds to the leptin receptor in the brain, which activates downstream signaling pathways that inhibit feeding and promote energy expenditure. This protein also has several endocrine functions, and is involved in the regulation of immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation and wound healing. Mutations in this gene and its regulatory regions cause severe obesity and morbid obesity with hypogonadism in human patients. A mutation in this gene has also been linked to type 2 diabetes mellitus development. [provided by RefSeq, Aug 2017]

LEP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a chain Leptin (size 145) in uniprot entity LEP_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000230.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

PP5

Variant 7-128254434-G-A is Pathogenic according to our data. Variant chr7-128254434-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2428497.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEP	NM_000230.3 linkuse as main transcript	c.175G>A	p.Gly59Ser	missense_variant	3/3	ENST00000308868.5
LEP	XM_005250340.6 linkuse as main transcript	c.172G>A	p.Gly58Ser	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEP	ENST00000308868.5 linkuse as main transcript	c.175G>A	p.Gly59Ser	missense_variant	3/3	1	NM_000230.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251130

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135764

show subpopulations

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461480

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Obesity due to congenital leptin deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing;in vitro

Division of Pediatric Endocrinology and Diabetes, Ulm University Medical Center

Jan 25, 2023

The Gly59Ser variant in LEP was detected in the homozygous state in a female child of two obese Arab parents who are first-degree cousins. The variant was absent from databases including the GME Variome, Exome Variant Server (EVS) (ESP6500SI-V2), and International Genome Sample Resource (IGSR). The affected child displayed intense hyperphagia, impaired satiety, rapid weight gain, and severe early-onset obesity with high circulating leptin levels matching the clinical presentation of congenital leptin dysfunction. in vitro functional studies demonstrated that the Gly59Ser variant does not affect leptin production, leptin secretion, or leptin receptor binding, but does impair leptin receptor activation. The leptin Gly59Ser variant triggers negligible signaling engaging the leptin receptor and behaves as a competitive antagonist in the presence of non-variant leptin. According to ACMG standards and guidelines (PMID: 25741868), the Gly59Ser variant can be classified as pathogenic (PS3/PM1/PM2/PP2/PP3/PP4). Diagnostic investigations excluded Prader-Willi and Bardet-Biedl syndromes. Of note, this variant was listed in gnomAD (v2.1.1) as previously detected in the heterozygous state in a single non-Finnish European. -

Leptin dysfunction

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

0.97

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.55

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.64

MutPred

0.75

Gain of disorder (P = 0.0491);

MVP

0.94

MPC

1.4

ClinPred

0.99

GERP RS

5.8

Varity_R

0.65

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over