Submissions for variant NM_019066.5(MAGEL2):c.1996dup (p.Gln666fs)

dbSNP: rs770374710

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000380351	SCV000329409	pathogenic	not provided	2022-03-17	criteria provided, single submitter	clinical testing	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)
Eurofins Ntd Llc (ga)	RCV000380351	SCV000703044	pathogenic	not provided	2016-11-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622753	SCV000740854	pathogenic	Inborn genetic diseases	2015-03-20	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000170356	SCV000746657	pathogenic	Schaaf-Yang syndrome	2017-05-12	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000170356	SCV000928360	pathogenic	Schaaf-Yang syndrome	2018-07-10	criteria provided, single submitter	clinical testing	PVS1, PS2, PP5
CeGaT Center for Human Genetics Tuebingen	RCV000380351	SCV001248891	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	MAGEL2: PS2, PS4, PVS1:Strong, PM1, PM2
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000170356	SCV001430737	pathogenic	Schaaf-Yang syndrome	2020-05-29	criteria provided, single submitter	research	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).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000380351	SCV001447276	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000380351	SCV001584125	pathogenic	not provided	2022-12-23	criteria provided, single submitter	clinical testing	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.
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV000170356	SCV001622605	pathogenic	Schaaf-Yang syndrome	2021-05-19	criteria provided, single submitter	clinical testing
3billion	RCV000170356	SCV002011949	pathogenic	Schaaf-Yang syndrome	2021-10-02	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000170356	SCV002017210	pathogenic	Schaaf-Yang syndrome	2022-11-07	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252015	SCV002523400	pathogenic	See cases	2019-12-17	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM2, PP1
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273971	SCV002558994	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV002277321	SCV002564471	pathogenic	Neurodevelopmental disorder	2022-01-21	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000170356	SCV002579037	pathogenic	Schaaf-Yang syndrome	2022-03-23	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000170356	SCV003807091	pathogenic	Schaaf-Yang syndrome	2022-11-12	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 moderated, PM1 moderated, PM6 moderated, PP1 strong
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000170356	SCV003919055	pathogenic	Schaaf-Yang syndrome	2023-04-20	criteria provided, single submitter	research
Daryl Scott Lab, Baylor College of Medicine	RCV000170356	SCV004102712	pathogenic	Schaaf-Yang syndrome	2023-11-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000170356	SCV004183408	pathogenic	Schaaf-Yang syndrome	2023-09-14	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000170356	SCV004242419	pathogenic	Schaaf-Yang syndrome	2024-01-05	criteria provided, single submitter	clinical testing	Criteria applied: PVS1_STR,PS2,PS4
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000380351	SCV005198711	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000170356	SCV005399980	pathogenic	Schaaf-Yang syndrome	2024-09-20	criteria provided, single submitter	clinical testing	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
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000170356	SCV005418569	pathogenic	Schaaf-Yang syndrome		criteria provided, single submitter	clinical testing	PVS1_Moderate+PS4+PS2_VeryStrong+PP4+PM2_Supporting
OMIM	RCV000170356	SCV000222765	pathogenic	Schaaf-Yang syndrome	2014-12-03	no assertion criteria provided	literature only
Department Of Pediatrics And Neonatology, Nagoya City University Graduate School Of Medical Sciences	RCV000170356	SCV000784669	pathogenic	Schaaf-Yang syndrome	2018-06-25	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000380351	SCV001742493	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000380351	SCV001800630	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000170356	SCV002034731	not provided	Schaaf-Yang syndrome		no assertion provided	literature only	Recurrent severe pathogenic variant
GenomeConnect - Brain Gene Registry	RCV003458348	SCV004176884	not provided	Schaaf-Yang syndrome; Prader-Willi-like syndrome		no assertion provided	phenotyping only	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/.