chr18-60371454-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_005912.3(MC4R):c.896C>A(p.Pro299His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,010 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P299S) has been classified as Uncertain significance.
Frequency
Consequence
NM_005912.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MC4R | NM_005912.3 | c.896C>A | p.Pro299His | missense_variant | 1/1 | ENST00000299766.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MC4R | ENST00000299766.5 | c.896C>A | p.Pro299His | missense_variant | 1/1 | NM_005912.3 | P1 | ||
ENST00000658928.1 | n.156+42109G>T | intron_variant, non_coding_transcript_variant | |||||||
ENST00000650201.1 | n.113+42109G>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251394Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135860
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727236
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74310
ClinVar
Submissions by phenotype
BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Nov 02, 2023 | PS3, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 10, 2022 | - - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 04, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects MC4R function (PMID: 16083993, 16752916, 20696697, 20826565, 25332687). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MC4R protein function. ClinVar contains an entry for this variant (Variation ID: 36488). This missense change has been observed in individual(s) with obesity (PMID: 12499395, 12851297, 18559663, 19091795, 24426828). This variant is present in population databases (rs52804924, gnomAD 0.002%). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 299 of the MC4R protein (p.Pro299His). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 28, 2023 | Identified in patients with early-onset obesity in published literature (Lubrano-Berthelier et al., 2003; Stutzmann et al., 2008); Published functional studies demonstrate a damaging effect (Ahituv et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); 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: 16752916, 17628007, 25332687, 20696697, 18559663, 24426828, 12499395, 19091795, 17357083, 31447099, 20826565, 34694010) - |
Obesity due to melanocortin 4 receptor deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 01, 2022 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Obesity Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
MC4R-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 13, 2024 | The MC4R c.896C>A variant is predicted to result in the amino acid substitution p.Pro299His. This variant has previously been reported in the heterozygous state in patients who presented with morbid obesity (Stutzmann et al. 2008. PubMed ID: 18559663; Lubrano-Berthelier et al. 2003. PubMed ID: 12499395). This variant was also reported in the apparently homozygous state in a child who presented with severe early-onset obesity; although genetic testing was not reported for either parent, the family history was significant for obesity in both parents (Pillai et al. 2014. PubMed ID: 24426828). Furthermore, in vitro studies indicate that the p.Pro299His change results in intracellular retention of the MC4R receptor and therefore disruption of α-MSH activation (Lubrano-Berthelier et al. 2003. PubMed ID: 12499395; Roubert et al. 2010. PubMed ID: 20696697). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. In summary, we classify this variant as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at