Submissions for variant NM_019066.5(MAGEL2):c.1922C>G (p.Pro641Arg)

dbSNP: rs556296973

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001356681	SCV003514070	uncertain significance	not provided	2025-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 641 of the MAGEL2 protein (p.Pro641Arg). This variant is present in population databases (rs556296973, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MAGEL2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1049948). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MAGEL2 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV004034468	SCV004902082	likely benign	Inborn genetic diseases	2023-11-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356681	SCV001551920	likely benign	not provided		no assertion criteria provided	clinical testing	The MAGEL2 p.Pro641Arg variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs556296973) and in control databases in 26 of 224764 chromosomes at a frequency of 0.0001157 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 10 of 16162 chromosomes (freq: 0.000619), African in 10 of 18598 chromosomes (freq: 0.000538), South Asian in 4 of 25864 chromosomes (freq: 0.000155) and European (non-Finnish) in 2 of 98328 chromosomes (freq: 0.00002), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish) or Other populations. Computational analyses (PolyPhen-2, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003416256	SCV004116668	uncertain significance	MAGEL2-related disorder	2024-03-11	no assertion criteria provided	clinical testing	The MAGEL2 c.1922C>G variant is predicted to result in the amino acid substitution p.Pro641Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.062% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.