Submissions for variant NM_019066.5(MAGEL2):c.1894G>A (p.Ala632Thr)

gnomAD frequency: 0.00003  dbSNP: rs777626175

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001573154	SCV004509824	uncertain significance	not provided	2023-08-06	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAGEL2 protein function. ClinVar contains an entry for this variant (Variation ID: 1206055). This missense change has been observed in individual(s) with Opitz trigonocephaly C syndrome (PMID: 28281571). 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 sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 632 of the MAGEL2 protein (p.Ala632Thr).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004785281	SCV005398561	uncertain significance	Schaaf-Yang syndrome	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_019066.4(MAGEL2):c.1894G>A in exon 1 of 1 of the MAGEL2 gene. The substitution is predicted to create a minor amino acid change from alanine to threonine at position 632 of the protein, NP_061939.3(MAGEL2):p.(Ala632Thr). The alanine at this position has low conservation (100 vertebrates, UCSC) and is located within the PAT1 domain. In silico software predicts this variant to be benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.001% (2 heterozygotes, 0 homozygotes). MAGEL2 is a maternally-imprinted gene (Schaaf, C.P. et al. (2013)). It has been previously reported on the maternal allele of a patient with Opitz trigonocephaly C syndrome (OTCS) which is predicted to be silenced due to gene imprinting (Urreizti, R. et al. (2017)). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573154	SCV001798581	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001573154	SCV001923665	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001573154	SCV001971922	likely benign	not provided		no assertion criteria provided	clinical testing