15-23645746-TG-TGG
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_019066.5(MAGEL2):c.1996dupC(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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_019066.5 frameshift
Scores
Clinical Significance
Conservation
Publications
- Schaaf-Yang syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MAGEL2 | NM_019066.5 | c.1996dupC | p.Gln666ProfsTer47 | frameshift_variant | Exon 1 of 1 | ENST00000650528.1 | NP_061939.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MAGEL2 | ENST00000650528.1 | c.1996dupC | p.Gln666ProfsTer47 | frameshift_variant | Exon 1 of 1 | NM_019066.5 | ENSP00000497810.1 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.0000208 AC: 4AN: 192088 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000422 AC: 6AN: 1421024Hom.: 0 Cov.: 32 AF XY: 0.00000427 AC XY: 3AN XY: 703230 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Schaaf-Yang syndrome Pathogenic:18Other:1
Criteria applied: PVS1_STR,PS2,PS4
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 25473036, 27195816, 27632685, 30302899). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000190122 / PMID: 25473036 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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).
ACMG classification criteria: PVS1 moderated, PM1 moderated, PM6 moderated, PP1 strong
PVS1, PS2, PP5
Recurrent severe pathogenic variant
The frameshift c.1996dup(p.Gln666ProfsTer47) variant in MAGEL2 gene has been reported previously in multiple individuals affected with Schaaf-Yang syndrome (Aten E, et al., 2016; Fountain MD, et al., 2017; Soden SE, et al., 2014). This variant has been reported to segregate with disease in related individuals. The p.Gln666ProfsTer47 variant is present with allele frequency of 0.002% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Glutamine 666, changes this amino acid to Proline residue, and creates a premature Stop codon at position 47 of the new reading frame, denoted p.Gln666ProfsTer47. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
PVS1_strong, PS3_strong, PS4_mod, PM2_supp
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
Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.
not provided Pathogenic:8
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)
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. 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. 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. ClinVar contains an entry for this variant (Variation ID: 190122). For these reasons, this variant has been classified as Pathogenic.
MAGEL2: PS2, PS4, PVS1:Strong, PM1, PM2
Neurodevelopmental delay Pathogenic:1
Inborn genetic diseases Pathogenic:1
See cases Pathogenic:1
ACMG classification criteria: PVS1, PS4, PM2, PP1
Neurodevelopmental disorder Pathogenic:1
Prader-Willi-like syndrome;C5575066:Schaaf-Yang syndrome Other:1
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at