ClinVar Miner

Submissions for variant NM_002361.4(MAG):c.61C>T (p.His21Tyr)

gnomAD frequency: 0.00001  dbSNP: rs370825816
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521071 SCV000620940 uncertain significance not provided 2017-09-18 criteria provided, single submitter clinical testing The H21Y variant in the MAG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H21Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret H21Y as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000652703 SCV000774574 uncertain significance Hereditary spastic paraplegia 75 2017-12-23 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 21 of the MAG protein (p.His21Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MAG-related disease. This variant is present in population databases (rs370825816, ExAC 0.02%).

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