ClinVar

Description

The m.5538G>A variant in MT-TW was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in three affected individuals in two families (PMID: 20708751, PMID: 29043143), however haplogroups were not provided as necessary to apply PS4_supporting. No instances of de novo inheritance have been reported. There has been only one report of multiple family members with this variant and only mother and proband were reported although variant heteroplasmy load did correlate with symptoms in proband and mother (PMID: 20708751). This variant is absent in the GenBank data set and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 76.70%, as does HmtVar with a score of 0.75 (PP3). In summary, there is not sufficient evidence to characterize this variant as pathogenic or benign, therefore it is characterized as a variant of uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. While this variant is reported in three affected individuals, absent from population databases, and predicted to effect tRNA function, additional evidence of pathogenicity is not yet present. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PM2_supporting, PP3.