ClinVar Genomic variation as it relates to human health

The LEPR c.1835G>A (p.Arg612His) missense variant has been reported in at least four studies in which it was found in a total of three individuals, two of whom are related, with severe childhood onset obesity. Specifically, the variant was reported in a homozygous state in one individual with childhood-onset morbid obesity, a family history of obesity with no variants found in the MC4R gene, and in a compound heterozygous state with a frameshift variant in a second individual with childhood-onset morbid obesity and hyperphagia (Farooqi et al. 2007; Albuquerque et al. 2014). The p.Arg612His variant was also reported in a heterozygous state in a third individual with severe obesity in whom a second variant was not identified, although only the leptin binding domain of the LEPR gene was sequenced (Branson et al. 2003; Potoczna et al. 2004). The variant was absent from 352 control alleles (Branson et al. 2003; Farooqi et al. 2007; Aloraifi et al. 2015) but is reported at a frequency of 0.004323 in the American population of the 1000 Genomes Project. Functional studies conducted in HEK293 cells showed that the p.Arg612His variant, which is located in the leptin binding domain, results in slightly reduced surface expression compared to the wild type protein. In addition, leptin binding and downstream signaling, as measured by STAT3, JAK2, and ERK1/2 phosphorylation, was impaired but not abolished (Farooqi et al. 2007; Kimber et al. 2008). Additionally, multiple in silico tools predict the p.Arg612His variant to have a deleterious effect. Based on the collective evidence, the p.Arg612His variant is classified as likely pathogenic for LEPR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Inconclusive segregation with disease.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.035%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:17229951, 18703626). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.56; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000631614). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 24611737). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 612 of the LEPR protein (p.Arg612His). This variant is present in population databases (rs144159890, gnomAD 0.08%). This missense change has been observed in individual(s) with leptin receptor deficiency (PMID: 17229951, 24611737). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 631614). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LEPR protein function. Experimental studies have shown that this missense change affects LEPR function (PMID: 18703626, 33221380). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The LEPR c.1835G>A variant is predicted to result in the amino acid substitution p.Arg612His. This variant has been reported once in the homozygous state and once in the compound heterozygous state with a second potentially pathogenic variant, in patients with severe early-onset obesity (Farooqi et al. 2007. PubMed ID: 17229951; Albuquerque et al. 2014. PubMed ID: 24611737; Zorn et al. 2022. PubMed ID: 35809703; Wabitsch et al. 2022. PubMed ID: 35528826). This variant has also been associated with severe obesity in several individuals for whom no second variant was found in LEPR; however, some of these studies did not sequence the full gene (Branson et al. 2003. PubMed ID: 12646666; Potoczna et al. 2004. PubMed ID: 15585384; Kleinendorst et al. 2018. PubMed ID: 29970488; Voigtmann et al. 2021. PubMed ID: 33221380). This variant is reported in 0.082% of alleles in individuals of Latino descent in gnomAD, which is more common than expected for a disease causing LEPR variant. Functional studies have come to conflicting conclusions regarding this variant's impact (Kimber et al. 2008. PubMed ID: 18703626; Farooqi et al. 2007. PubMed ID: 17229951; Voigtmann et al. 2021. PubMed ID: 33221380; Shah et al. 2023. PubMed ID: 36864747). Of note, one compound heterozygous patient treated with setmelanotide did not experience weight loss (Wabitsch et al. 2022. PubMed ID: 35528826). Although we suspect that this variant may be pathogenic, the clinical significance of this variant is classified as uncertain at this time due to insufficient functional and genetic evidence.