VCV000190122.66 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(28)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 190122 Accession: VCV000190122.66

Type and length

Duplication, 1 bp

Location

Cytogenetic: 15q11.2 15: 23645746-23645747 (GRCh38) [ NCBI UCSC ] 15: 23890893-23890894 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Oct 20, 2024	Jan 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_019066.5(MAGEL2):c.1996dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_019066.5:c.1996dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_061939.3:p.Gln666fs	frameshift
NM_019066.5:c.1996dupC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_019066.4:c.1996dupC
NC_000015.10:g.23645753dup
NC_000015.9:g.23890900dup
NG_016776.1:g.7100dup
LRG_1046:g.7100dup
LRG_1046t1:c.1996dup	LRG_1046p1:p.Gln666fs

... more HGVS ... less HGVS

Protein change

Q666fs

Other names

Canonical SPDI

NC_000015.10:23645746:GGGGGGG:GGGGGGGG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA199566 OMIM: 605283.0005 dbSNP: rs770374710 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MAGEL2		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	1046	1350

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Schaaf-Yang syndrome	Pathogenic (15)	criteria provided, multiple submitters, no conflicts	Jan 5, 2024	RCV000170356.33
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jun 1, 2023	RCV000380351.43
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Mar 20, 2015	RCV000622753.4
Neurodevelopmental delay	Pathogenic (1)	criteria provided, single submitter	-	RCV002273971.3
See cases	Pathogenic (1)	criteria provided, single submitter	Dec 17, 2019	RCV002252015.3
Neurodevelopmental disorder	Pathogenic (1)	criteria provided, single submitter	Jan 21, 2022	RCV002277321.2
Prader-Willi-like syndrome Schaaf-Yang syndrome	not provided (1)	no classification provided	-	RCV003458348.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447276.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Absent speech (present) , Global developmental delay (present) , Arthrogryposis multiplex congenita (present) , Hydronephrosis (present) , Bilateral talipes equinovarus (present) , Anal stenosis (present) Sex: female
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental delay Affected status: yes Allele origin: unknown	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV002558994.1 First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022
Pathogenic (Mar 20, 2015)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000740854.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (1) PubMed: 25473036 Observation 1: Number of individuals with the variant: 1 Clinical Features: Congenital contracture (present) , Global developmental delay (present) , Nystagmus (present) , Central apnea (present) , Diabetes insipidus (present) , Flexion contracture (present) , Overlapping … (more) Congenital contracture (present) , Global developmental delay (present) , Nystagmus (present) , Central apnea (present) , Diabetes insipidus (present) , Flexion contracture (present) , Overlapping toe (present) , Decreased muscle mass (present) , Protruding ear (present) , Ptosis (present) , Micrognathia (present) , Tongue thrusting (present) , Short nose (present) , Anteverted nares (present) , Underdeveloped nasal alae (present) , Wide mouth (present) , Joint contracture of the hand (present) , Abnormality of the lip (present) , Prominent fingertip pads (present) , Feeding difficulties (present) , Rod-cone dystrophy (present) (less) Sex: female Ethnicity/Population group: Unknown Observation 2: Number of individuals with the variant: 1 Clinical Features: Arthrogryposis multiplex congenita (present) , Global developmental delay (present) , Flexion contracture (present) , Large forehead (present) , Midface retrusion (present) , Micrognathia (present) , … (more) Arthrogryposis multiplex congenita (present) , Global developmental delay (present) , Flexion contracture (present) , Large forehead (present) , Midface retrusion (present) , Micrognathia (present) , Glossoptosis (present) , High palate (present) , Downslanted palpebral fissures (present) , Exotropia (present) , Long eyelashes (present) , Hypertelorism (present) , Single transverse palmar crease (present) , Generalized hypotonia (present) , Camptodactyly (present) , Secundum atrial septal defect (present) , Cryptorchidism (present) , Aplasia/hypoplasia of the extremities (present) (less) Sex: male Ethnicity/Population group: Unknown Observation 3: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Caucasian
Pathogenic (Sep 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Schaaf-Yang syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004183408.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Nov 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Schaaf-Yang syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017210.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 23, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001584125.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 25473036‚ 27195816‚ 27632685 Comment: This sequence change creates a premature translational stop signal (p.Gln666Profs47) in the MAGEL2 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Gln666Profs47) 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. (less)
Pathogenic (Jun 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248891.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Comment: MAGEL2: PS2, PS4, PVS1:Strong, PM1, PM2 Number of individuals with the variant: 3
Pathogenic (May 12, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Schaaf-Yang syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV000746657.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017	Observation 1: Number of individuals with the variant: 1 Clinical Features: Tongue thrusting (present) , Temperature instability (present) , Tapered finger (present) , Short toe (present) , Short stature (present) , Short palm (present) , Short … (more) Tongue thrusting (present) , Temperature instability (present) , Tapered finger (present) , Short toe (present) , Short stature (present) , Short palm (present) , Short foot (present) , Severe global developmental delay (present) , Seizures (present) , Premature birth (present) , Poor suck (present) , Poor eye contact (present) , Oromotor apraxia (present) , Oligohydramnios (present) , Myopia (present) , Muscular hypotonia (present) , Mild microcephaly (present) , Intrauterine growth retardation (present) , Hypothyroidism (present) , Hypernatremia (present) , Hyperhidrosis (present) , Feeding difficulties (present) , Esotropia (present) , EEG abnormality (present) , Dysphagia (present) , Depressed nasal bridge (present) , Bradycardia (present) , Aspiration (present) , Absent speech (present) , Abnormality of the skeletal system (present) , Abnormality of the cornea (present) , Abnormality of brain morphology (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: Hispanic Comment on evidence: This individual is heterozygous for this variant, which was confirmed by Sanger sequencing. Sanger sequencing analysis of this region in the parental samples for this … (more) This individual is heterozygous for this variant, which was confirmed by Sanger sequencing. Sanger sequencing analysis of this region in the parental samples for this individual did not detect the c.1996dupC (p.Q666fs) pathogenic variant, suggesting that this change arose de novo in the patient. Subsequent methylation studies showed that the pathogenic change occurred on the patientâ€™s paternal allele. (less) Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2016-08-19 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Visual impairment (present) , Ventriculomegaly (present) , Trigonocephaly (present) , Strabismus (present) , Small hand (present) , Short foot (present) , Scoliosis (present) , Retrognathia … (more) Visual impairment (present) , Ventriculomegaly (present) , Trigonocephaly (present) , Strabismus (present) , Small hand (present) , Short foot (present) , Scoliosis (present) , Retrognathia (present) , Precocious puberty (present) , Polyhydramnios (present) , Pectus excavatum (present) , Panhypopituitarism (present) , Overlapping toe (present) , Overlapping fingers (present) , Osteopenia (present) , Obstructive sleep apnea syndrome (present) , Nystagmus (present) , Noncommunicating hydrocephalus (present) , Neonatal respiratory distress (present) , Muscular hypotonia of the trunk (present) , Midface retrusion (present) , Microphthalmia (present) , Laryngomalacia (present) , Joint hypermobility (present) , Joint contracture of the hand (present) , Inability to walk (present) , Hypoxemia (present) , Hypopituitarism (present) , Hypertonia (present) , Hydronephrosis (present) , Humerus varus (present) , High palate (present) , Hemihypertrophy of lower limb (present) , Hand clenching (present) , Growth hormone deficiency (present) , Global developmental delay (present) , Gastrostomy tube feeding in infancy (present) , Frontal bossing (present) , Distal arthrogryposis (present) , Dilation of lateral ventricles (present) , Decreased circulating cortisol level (present) , Craniosynostosis (present) , Complete duplication of thumb phalanx (present) , Clinodactyly of the 5th toe (present) , Chronic lung disease (present) , Central hypothyroidism (present) , Neurohypophyseal diabetes insipidus (present) , Camptodactyly (present) , Caesarian section (present) , Adrenal insufficiency (present) , Absent speech (present) , Absent frontal sinuses (present) , Absent distal interphalangeal creases (present) , Abnormality of the cerebral white matter (present) , Abnormality of inferior oblique extraocular muscle (present) , Abnormal pupillary light reflex (present) , Abnormal delivery (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: White Comment on evidence: The c.1996dupC is a frameshift variant, predicted to result in loss of function in the MAGEL2 gene where loss of function is a known mechanism … (more) The c.1996dupC is a frameshift variant, predicted to result in loss of function in the MAGEL2 gene where loss of function is a known mechanism of Schaaf-Yang syndrome. The c.1996dupC variant has been observed in multiple, unrelated, affected individuals with Schaaf-Yang syndrome. The variant appears to be de novo; it was not observed in either of the parental samples. (less) Testing laboratory: HudsonAlpha Clinical Services Lab, LLC, HudsonAlpha Clinical Services Lab, LLC Date variant was reported to submitter: 2017-05-12 Testing laboratory interpretation: Pathogenic
Pathogenic (Nov 14, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000703044.2 First in ClinVar: Sep 30, 2017 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MAGEL2 Sex: mixed
Pathogenic (Jul 10, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Schaaf-Yang syndrome Affected status: yes Allele origin: de novo	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV000928360.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019	Comment: PVS1, PS2, PP5
Pathogenic (May 29, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Schaaf-Yang syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001430737.1 First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/657e2b63-4031-4a08-86f0-dfd3de8bee7e Comment: 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 … (more) 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 proteinâ€™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). (less)
Pathogenic (May 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Schaaf-Yang syndrome Affected status: yes Allele origin: paternal, de novo	Center for Molecular Medicine, Children’s Hospital of Fudan University Accession: SCV001622605.1 First in ClinVar: May 23, 2021 Last updated: May 23, 2021	Observation 1: Sex: female Observation 2: Sex: female
Pathogenic (Oct 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Schaaf-Yang syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002011949.1 First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021	Publications: PubMed (4) PubMed: 25473036‚ 27195816‚ 27632685‚ 30302899 Comment: 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 … (more) 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. (less) Clinical Features: Flexion contracture (present) , Gastroparesis (present) , Flexion contracture (present) , Fetal growth restriction (present) , Clubfoot (present) , Growth delay (present) , Congenital muscular … (more) Flexion contracture (present) , Gastroparesis (present) , Flexion contracture (present) , Fetal growth restriction (present) , Clubfoot (present) , Growth delay (present) , Congenital muscular dystrophy (present) , Short stature (present) , Distal arthrogryposis (present) , Failure to thrive (present) , Generalized hypotonia (present) , High, narrow palate (present) , Neonatal hypotonia (present) , Gastroesophageal reflux (present) (less)
Pathogenic (Dec 17, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002523400.1 First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022	Comment: ACMG classification criteria: PVS1, PS4, PM2, PP1 Clinical Features: Clubfoot (present) , Small nail (present) , Hypomimic face (present) , High, narrow palate (present) , Camptodactyly (present) Geographic origin: Brazil
Pathogenic (Jan 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes Accession: SCV002564471.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Pathogenic (Mar 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Schaaf-Yang syndrome Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579037.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS2, PM2_SUP, PP1	Number of individuals with the variant: 1
Pathogenic (Mar 17, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329409.8 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Nov 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Schaaf-Yang syndrome Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807091.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 moderated, PM1 moderated, PM6 moderated, PP1 strong Number of individuals with the variant: 1 Clinical Features: Tapered finger (present) , Mandibular prognathia (present) , Small hand (present) , Trigonocephaly (present) , Malar flattening (present) , Strabismus (present) , Neonatal sepsis (present) … (more) Tapered finger (present) , Mandibular prognathia (present) , Small hand (present) , Trigonocephaly (present) , Malar flattening (present) , Strabismus (present) , Neonatal sepsis (present) , Camptodactyly (present) , Low posterior hairline (present) , Pes planus (present) , Short stature (present) , Autism (present) , Poor suck (present) , Prominent metopic ridge (present) , Metopic synostosis (present) , Upslanted palpebral fissure (present) , Intellectual disability (present) , Small earlobe (present) , Smooth philtrum (present) , Webbed neck (present) , Short philtrum (present) , Short palm (present) (less) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Apr 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Schaaf-Yang syndrome Affected status: yes Allele origin: de novo	Duke University Health System Sequencing Clinic, Duke University Health System Accession: SCV003919055.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023
Pathogenic (Nov 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Schaaf-Yang syndrome Affected status: yes Allele origin: paternal	Daryl Scott Lab, Baylor College of Medicine Accession: SCV004102712.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023
Pathogenic (Jan 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Schaaf-Yang syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004242419.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: Criteria applied: PVS1_STR,PS2,PS4 Clinical Features: Respiratory acidosis (present) , Metabolic alkalosis (present) , Large fontanelles (present) , Spasticity (present) , Hypernatremia (present) , Hypotonia (present) , Abnormality of the outer … (more) Respiratory acidosis (present) , Metabolic alkalosis (present) , Large fontanelles (present) , Spasticity (present) , Hypernatremia (present) , Hypotonia (present) , Abnormality of the outer ear (present) , Camptodactyly (present) , Severe global developmental delay (present) (less) Sex: male
Pathogenic (Jul 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198711.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jun 25, 2018)	no assertion criteria provided Method: clinical testing	Schaaf-Yang syndrome Affected status: yes Allele origin: de novo	Department Of Pediatrics And Neonatology, Nagoya City University Graduate School Of Medical Sciences Accession: SCV000784669.1 First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018	Number of individuals with the variant: 1 Age: 0-9 years Sex: male Ethnicity/Population group: Asian Geographic origin: Japan
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800630.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001742493.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (Dec 03, 2014)	no assertion criteria provided Method: literature only	SCHAAF-YANG SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000222765.5 First in ClinVar: May 09, 2015 Last updated: Nov 29, 2021	Publications: PubMed (5) PubMed: 25473036‚ 27195816‚ 29599419‚ 30302899‚ 29660409 Comment on evidence: In 2 sisters with Schaaf-Yang syndrome (SHFYNG; 615547), Soden et al. (2014) identified a heterozygous 1-bp duplication (c.1996dupC) in the MAGEL2 gene, predicted to result … (more) In 2 sisters with Schaaf-Yang syndrome (SHFYNG; 615547), Soden et al. (2014) identified a heterozygous 1-bp duplication (c.1996dupC) in the MAGEL2 gene, predicted to result in a frameshift, premature termination (Gln666ProfsTer47), and a loss of function. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was undetectable in the parents, suggesting gonadal mosaicism of this paternally expressed gene. Fountain et al. (2017) identified a heterozygous c.1996dupC mutation in 11 patients with SHFYNG from 7 unrelated families; in 5 of these patients the mutation occurred de novo. All of these patients were ascertained based on genotype from whole-exome or direct Sanger sequencing through multiple research-based centers or laboratories. All mutations were confirmed by Sanger sequencing. In a patient with Schaaf-Yang syndrome, who had been clinically diagnosed with Chitayat-Hall syndrome, Jobling et al. (2018) identified heterozygosity for the c.1996dupC mutation in the MAGEL2 gene. Among 78 patients with Schaaf-Yang syndrome reported by McCarthy et al. (2018), 35 (45%) had the c.1996dupC mutation in the MAGEL2 gene. The authors compared these patients to 38 patients with MAGEL2 mutations in other locations and found that patients with c.1996dupC had a higher prevalence of joint contractures, feeding difficulties, and respiratory problems, as well as more severe intellectual disability/developmental delay. In a patient with Schaaf-Yang syndrome and chronic intestinal pseudoobstruction, Bayat et al. (2018) identified heterozygosity for the c.1996dupC in the MAGEL2 gene. (less)
not provided (-)	no classification provided Method: literature only	Prader-Willi-like syndrome Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV002034731.2 First in ClinVar: Dec 18, 2021 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 30302899 BookShelf: NBK567492 BookShelf: NBK567492 Comment: Recurrent severe pathogenic variant
not provided (-)	no classification provided Method: phenotyping only	Schaaf-Yang syndrome Prader-Willi-like syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: yes Allele origin: de novo	GenomeConnect - Brain Gene Registry Accession: SCV004176884.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: 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 … (more) 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/. (less) Clinical Features: Decreased fetal movement (present) , Neonatal hypotonia (present) , Neurodevelopmental delay (present) , Intellectual disability (present) , Short stature (present) , Arthrogryposis multiplex congenita (present) Indication for testing: Diagnostic Age: 10-19 years Sex: female Method: Exome Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2018-09-08 Testing laboratory interpretation: Pathogenic
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Comment:

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.

Comment:

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 proteinâ€™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).

Comment:

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.

Comment:

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)

Comment:

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/.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Schaaf-Yang Syndrome.	Adam MP	-	2021	PMID: 33570896
MAGEL2-related disorders: A study and case series.	Patak J	Clinical genetics	2019	PMID: 31397880
Schaaf-Yang syndrome overview: Report of 78 individuals.	McCarthy J	American journal of medical genetics. Part A	2018	PMID: 30302899
Chronic intestinal pseudo-obstruction syndrome and gastrointestinal malrotation in an infantwith schaaf-yang syndrome - Expanding the phenotypic spectrum.	Bayat A	European journal of medical genetics	2018	PMID: 29660409
Chitayat-Hall and Schaaf-Yang syndromes:a common aetiology: expanding the phenotype of MAGEL2-related disorders.	Jobling R	Journal of medical genetics	2018	PMID: 29599419
The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.	Fountain MD	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27195816
Imprinting: the Achilles heel of trio-based exome sequencing.	Aten E	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 27632685
Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.	Soden SE	Science translational medicine	2014	PMID: 25473036
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MAGEL2	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/657e2b63-4031-4a08-86f0-dfd3de8bee7e	-	-	-	-

Text-mined citations for rs770374710 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs770374710 ...