Variant: NC_012920.1:m.5538G>A

CA913179793

689930 (ClinVar)

Gene: MT-TW

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: ec54990f-55b6-4d09-b0af-aa8fde5497ab

HGVS expressions

NC_012920.1:m.5538G>A
J01415.2:m.5538G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting PP3

• Not Met criteria codes: PVS1 PS4 PS2 PP4 PP1 PM5

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

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.

Met criteria codes

• PM2_Supporting: This variant is absent in the GenBank data set and gnomAD v3.1.2 (PM2_supporting).
• PP3: 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).

Not Met criteria codes

• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Although reported in PMIDs 20708751 and 29043143, there is no mention of haplogroup of these individuals or if they are or are not related.
• PS2: Inherited in Malfatti et al., 2010 - PMID: 20708751; no mention of parental testing in Lim et al., 2017 - PMID: 29043143
• PP4: In PMID: 20708751: proband muscle 60% CI activity, 40% CIV activity; mother muscle 30% CI activity
• PP1: Only mother and proband reported in one family (PMID: 20708751).
• PM5: No other variants reported at this position.

Approved on: 2021-10-26

Published on: 2021-10-26