NM_019066.5(MAGEL2):c.1996dup (p.Gln666fs) AND not provided

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Jun 1, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000380351.43

Allele description [Variation Report for NM_019066.5(MAGEL2):c.1996dup (p.Gln666fs)]

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

Gene:

MAGEL2:MAGE family member L2 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

15q11.2

Genomic location:

Preferred name:

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

HGVS:

NC_000015.10:g.23645753dup
NG_016776.1:g.7100dup
NM_019066.5:c.1996dupMANE SELECT
NP_061939.3:p.Gln666fs
LRG_1046t1:c.1996dup
LRG_1046:g.7100dup
LRG_1046p1:p.Gln666fs
NC_000015.9:g.23890893_23890894insG
NC_000015.9:g.23890900dup
NM_019066.4:c.1996dup
NM_019066.4:c.1996dupC
NM_019066.5(MAGEL2):c.1996dupMANE SELECT
NM_019066.5:c.1996dupCMANE SELECT
p.Gln666fs
p.Q666fs

Protein change:

Q666fs

Links:

OMIM: 605283.0005; dbSNP: rs770374710

NCBI 1000 Genomes Browser:

rs770374710

Molecular consequence:

NM_019066.5:c.1996dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329409	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 17, 2022)	germline	clinical testing	Citation Link,
SCV000703044	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Nov 14, 2016)	germline	clinical testing	Citation Link,
SCV001248891	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jun 1, 2023)	germline	clinical testing	Citation Link,
SCV001447276	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001584125	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 23, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25473036, 27195816, 27632685, 28492532
SCV001742493	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001800630	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV005198711	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.

Soden SE, Saunders CJ, Willig LK, Farrow EG, Smith LD, Petrikin JE, LePichon JB, Miller NA, Thiffault I, Dinwiddie DL, Twist G, Noll A, Heese BA, Zellmer L, Atherton AM, Abdelmoity AT, Safina N, Nyp SS, Zuccarelli B, Larson IA, Modrcin A, Herd S, et al.

Sci Transl Med. 2014 Dec 3;6(265):265ra168. doi: 10.1126/scitranslmed.3010076.

PubMed [citation]

PMID:: 25473036
PMCID:: PMC4286868

The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.

Fountain MD, Aten E, Cho MT, Juusola J, Walkiewicz MA, Ray JW, Xia F, Yang Y, Graham BH, Bacino CA, Potocki L, van Haeringen A, Ruivenkamp CA, Mancias P, Northrup H, Kukolich MK, Weiss MM, van Ravenswaaij-Arts CM, Mathijssen IB, Levesque S, Meeks N, Rosenfeld JA, et al.

Genet Med. 2017 Jan;19(1):45-52. doi: 10.1038/gim.2016.53. Epub 2016 May 19. Erratum in: Genet Med. 2016 Oct;18(10):1066. doi: 10.1038/gim.2016.114.

PubMed [citation]

PMID:: 27195816
PMCID:: PMC5116288

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000329409.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000703044.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001248891.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

Description

MAGEL2: PS2, PS4, PVS1:Strong, PM1, PM2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447276.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001584125.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001742493.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV001800630.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198711.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 30, 2024

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