Submissions for variant NM_019066.5(MAGEL2):c.3449_3450del (p.Phe1150fs)

dbSNP: rs998860333

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002266508	SCV002547518	likely pathogenic	Schaaf-Yang syndrome	2022-05-24	criteria provided, single submitter	clinical testing	Variant summary: MAGEL2 c.3449_3450delTT (p.Phe1150TrpfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in association with Schaaf-Yang syndrome in HGMD and classified as likely pathogenic in Clinvar. The variant allele was found at a frequency of 4e-06 in 248912 control chromosomes. c.3449_3450delTT has been reported in the literature in an individual affected with Schaaf-Yang Syndrome (Ahn_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003096041	SCV003201476	uncertain significance	not provided	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe1150Trpfs*4) in the MAGEL2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 100 amino acid(s) of the MAGEL2 protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of Schaaf-Yang syndrome (PMID: 33371171). ClinVar contains an entry for this variant (Variation ID: 1696363). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.