15-23645746-TG-TGG
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_019066.5(MAGEL2):c.1996_1997insC(p.Gln666ProfsTer47) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000422 in 1,421,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000042 ( 0 hom. )
Consequence
MAGEL2
NM_019066.5 frameshift
NM_019066.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.06
Genes affected
MAGEL2 (HGNC:6814): (MAGE family member L2) Prader-Willi syndrome (PWS) is caused by the loss of expression of imprinted genes in chromosome 15q11-q13 region. Affected individuals exhibit neonatal hypotonia, developmental delay, and childhood-onset obesity. Necdin (NDN), a gene involved in the terminal differentiation of neurons, localizes to this region of the genome and has been implicated as one of the genes responsible for the etiology of PWS. This gene is structurally similar to NDN, is also localized to the PWS chromosomal region, and is paternally imprinted, suggesting a possible role for it in PWS. [provided by RefSeq, Oct 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PP5
Variant 15-23645746-T-TG is Pathogenic according to our data. Variant chr15-23645746-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 190122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MAGEL2 | NM_019066.5 | c.1996_1997insC | p.Gln666ProfsTer47 | frameshift_variant | 1/1 | ENST00000650528.1 | NP_061939.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MAGEL2 | ENST00000650528.1 | c.1996_1997insC | p.Gln666ProfsTer47 | frameshift_variant | 1/1 | NM_019066.5 | ENSP00000497810 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000422 AC: 6AN: 1421024Hom.: 0 Cov.: 32 AF XY: 0.00000427 AC XY: 3AN XY: 703230
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GnomAD4 genome
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:28Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Schaaf-Yang syndrome Pathogenic:16Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PVS1_Moderate+PS4+PS2_VeryStrong+PP4+PM2_Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 20, 2024 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Schaaf-Yang syndrome (MIM#615547). Multiple premature termination codon variants have previously been reported in this gene (ClinVar, DECIPHER) . (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0113 - This gene is known to be maternally imprinted (OMIM). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative truncating variant at the same position has been observed in gnomAD (v2) Gln666Serfs*36 (3 heterozygotes, 0 homozygotes). (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (PMID 27195816). (SP) 0701 - Other PTC variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in clinical cases (ClinVar; PMID 27195816, PMID 32021601, PMID 33371171). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status, confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 03, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Nov 12, 2022 | ACMG classification criteria: PVS1 moderated, PM1 moderated, PM6 moderated, PP1 strong - |
| Pathogenic, no assertion criteria provided | clinical testing | Department Of Pediatrics And Neonatology, Nagoya City University Graduate School Of Medical Sciences | Jun 25, 2018 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | Recurrent severe pathogenic variant - |
| Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | May 12, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 14, 2023 | - - |
| Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 29, 2020 | The heterozygous p.Gln666ProfsTer47 variant in MAGEL2 was identified by our study in 1 individual with Schaaf-Yang syndrome (Prader-Willi-like syndrome). Trio genome analysis showed this variant to be de novo. The variant has been reported in 7 individuals with Schaaf-Yang syndrome (including the one from our study), segregated with disease in 3 affected relatives from 2 families (PMID: 25473036, 27195816, 31397880). Data from large population studies is insufficient to assess the frequency of this variant. This variant has also been reported in ClinVar (Variation ID#: 190122) as pathogenic by multiple labs. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 666 and leads to a premature termination codon 47 amino acids downstream. This gene is a single exon gene and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. While there is some evidence to suggest that heterozygous loss of function of the MAGEL2 gene is a disease mechanism in Schaaf-Yang syndrome, this association is not yet strongly established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). Multiple variants in the same region as p.Gln666ProfsTer47 have been reported in association with disease in the literature, suggesting that this variant is in a hot spot and supports pathogenicity (PMID: 31397880). In summary, this variant meets criteria to be classified as pathogenic for Schaaf-Yang syndrome in an autosomal dominant manner based on the presence of multiple probands with disease including a de novo case and the predicted loss of function effect of this variant. ACMG/AMP Criteria applied: PS2, PVS1_moderate, PM1, PS4_supporting, PP1 (Richards 2015). - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 23, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Daryl Scott Lab, Baylor College of Medicine | Nov 10, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 07, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been observed in at least four similarly affected unrelated individuals (PMID: 30302899, 25473036, 27195816, 27632685). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Molecular Medicine, Children’s Hospital of Fudan University | May 19, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 05, 2024 | Criteria applied: PVS1_STR,PS2,PS4 - |
| Pathogenic, criteria provided, single submitter | research | Duke University Health System Sequencing Clinic, Duke University Health System | Apr 20, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Jul 10, 2018 | PVS1, PS2, PP5 - |
not provided Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 13, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 14, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 23, 2022 | This sequence change creates a premature translational stop signal (p.Gln666Profs*47) in the MAGEL2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 584 amino acid(s) of the MAGEL2 protein. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 190122). This premature translational stop signal has been observed in individual(s) with Schaaf-Yang syndrome (PMID: 25473036, 27195816, 27632685). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 17, 2022 | Reported to be the most common pathogenic variant in the MAGEL2 gene (Fountain et al., 2017; Jobling et al., 2018); Inheritance from unaffected fathers, including a mosaic father, has been reported, as has suspected germline mosaicism (Soden et al., 2014; Aten et al., 2016; Palomares-Bralo et al., 2017; Jobling et al., 2018); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 584 amino acids are lost and replaced with 46 incorrect amino acids; This variant is associated with the following publications: (PMID: 28640240, 25473036, 28281571, 27632685, 29660409, 29599419, 29581464, 27195816, 29496979, 30859550, 31504653, 31791363, 31397880, 31607746, 33076953, 34008892) - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2023 | MAGEL2: PS2, PS4, PVS1:Strong, PM1, PM2 - |
Neurodevelopmental delay Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2015 | - - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 17, 2019 | ACMG classification criteria: PVS1, PS4, PM2, PP1 - |
Neurodevelopmental disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Jan 21, 2022 | - - |
Prader-Willi-like syndrome;C5575066:Schaaf-Yang syndrome Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | Variant classified as Pathogenic and reported on 09-08-2018 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. - |
Computational scores
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SpliceAI score (max)
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