15-23645746-TG-TGG

Variant names:

• chr15-23645746-T-TG
• rs770374710
• NM_019066.5:c.1996dupC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_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. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:28 O:2
• 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]

ACMG classification

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 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 Cov.: 32

GnomAD4 exome AF: 0.00000422 AC: 6 AN: 1421024 Hom.: 0 Cov.: 32 AF XY: 0.00000427 AC XY: 3 AN XY: 703230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000797

Gnomad4 NFE exome AF: 9.15e-7

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Schaaf-Yang syndrome Pathogenic:16 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	May 19, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 03, 2014	- -
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	Revvity Omics, Revvity	Nov 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 23, 2022	- -
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	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 -
not provided, no classification provided	literature only	GeneReviews	-	Recurrent severe pathogenic variant -
Pathogenic, no assertion criteria provided	clinical testing	Department Of Pediatrics And Neonatology, Nagoya City University Graduate School Of Medical Sciences	Jun 25, 2018	- -
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	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jul 10, 2018	PVS1, PS2, PP5 -
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	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion, Medical Genetics	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	Undiagnosed Diseases Network, NIH	May 12, 2017	- -
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 -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
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, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	MAGEL2: PS2, PS4, PVS1:Strong, PM1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2024	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. -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs770374710; hg19: chr15-23890893;