VCV000013986.3 - ClinVar

NM_000230.3(LEP):c.398del (p.Gly133fs)

Germline

Classification

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.

(2)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000230.3(LEP):c.398del (p.Gly133fs)

Variation ID: 13986 Accession: VCV000013986.3

Type and length

Deletion, 1 bp

Location

Cytogenetic: 7q32.1 7: 128254652 (GRCh38) [ NCBI UCSC ] 7: 127894705 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Apr 4, 2013	Jul 23, 2024	Jul 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000230.3:c.398del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000221.1:p.Gly133fs	frameshift
NM_000230.2:c.398del
NC_000007.14:g.128254657del
NC_000007.13:g.127894710del
NG_007450.1:g.18380del

... more HGVS ... less HGVS

Protein change

G133fs

Other names

Canonical SPDI

NC_000007.14:128254651:GGGGGG:GGGGG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 164160.0001 VarSome

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
Gene	OMIM	HI score Help 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.
LEP		-	-	GRCh38 GRCh37	128	155

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.
Obesity due to congenital leptin deficiency	Pathogenic (1)	no assertion criteria provided	Oct 1, 2004	RCV000015023.26
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 11, 2024	RCV004589513.1

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 Help 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.
Pathogenic (Jul 11, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005078994.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: Published functional studies demonstrate a damaging effect where mutant leptin is not efficiently secreted, as compared to control leptin, and serum levels from homozygous patients … (more) Published functional studies demonstrate a damaging effect where mutant leptin is not efficiently secreted, as compared to control leptin, and serum levels from homozygous patients show no expression of the protein (PMID: 9202122); Frameshift variant predicted to result in protein truncation as the last 35 amino acids are lost and replaced with 14 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 9202122, 15472169, 24041679, 22463805, 29101506, 38470203, 32349990, 37659411, 36825860, 36121795) (less)
Pathogenic (Oct 01, 2004)	no assertion criteria provided Method: literature only	LEPTIN DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035279.2 First in ClinVar: Apr 04, 2013 Last updated: May 06, 2019	Publications: PubMed (3) PubMed: 9202122‚ 12393845‚ 15472169 Comment on evidence: In 2 morbidly obese cousins with very low serum leptin levels (LEPD; 614962) from an inbred Pakistani kindred, Montague et al. (1997) found homozygosity for … (more) In 2 morbidly obese cousins with very low serum leptin levels (LEPD; 614962) from an inbred Pakistani kindred, Montague et al. (1997) found homozygosity for a deletion of a guanine nucleotide in the leptin gene: there were 5 rather than the expected 6 guanine nucleotides present between nucleotides 393 and 398. The mutation disrupted the reading frame of the leptin gene, leading to the introduction of 14 aberrant amino acids after gly132 in the leptin polypeptide, followed by a premature stop codon. Farooqi et al. (2002) described a child from a consanguineous family of Pakistani origin living in the United Kingdom who was homozygous for the guanine deletion in codon 133 of leptin (delta-G133). The family was not known to be related to the family identified by Montague et al. (1997) over at least 5 generations. Leptin deficiency was associated with reduced numbers of circulating CD4+ T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration. In a child of consanguineous Pakistani parents in Canada who presented with severe hyperphagia and obesity, Gibson et al. (2004) found homozygosity for the delta-133G mutation in leptin. The family originated from the same area of Pakistan as the 2 United Kingdom families reported by Montague et al. (1997) and Farooqi et al. (2002), but was not known to be related over 4 generations. (less)

Comment:

Published functional studies demonstrate a damaging effect where mutant leptin is not efficiently secreted, as compared to control leptin, and serum levels from homozygous patients show no expression of the protein (PMID: 9202122); Frameshift variant predicted to result in protein truncation as the last 35 amino acids are lost and replaced with 14 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 9202122, 15472169, 24041679, 22463805, 29101506, 38470203, 32349990, 37659411, 36825860, 36121795)

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy.	Gibson WT	The Journal of clinical endocrinology and metabolism	2004	PMID: 15472169
Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency.	Farooqi IS	The Journal of clinical investigation	2002	PMID: 12393845
Congenital leptin deficiency is associated with severe early-onset obesity in humans.	Montague CT	Nature	1997	PMID: 9202122

Text-mined citations for this variant ...

Record last updated Jul 23, 2024

ClinVar Genomic variation as it relates to human health

NM_000230.3(LEP):c.398del (p.Gly133fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...