Variant: m.4332G>A

CA254844

9616 (ClinVar)

Gene: MT-TQ

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: a4ab91de-b482-4f5a-b85e-0759200302f4

Approved on: 2023-01-23

Published on: 2023-03-15

HGVS expressions

NC_012920.1:m.4332G>A
J01415.2:m.4332G>A

Uncertain Significance

• Met criteria codes: PS3_Supporting PM2_Supporting PP3

• Not Met criteria codes: PM6 BS4 PS4 PS2 PP1

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.4332G>A variant in MT-TQ has been reported in one individual from one family to date (PMID: 11171912), in a man with an atypical presentation of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). This individual had hearing loss beginning in his 20s and a stroke-like episode in his 40s. Muscle biopsy showed ragged red fibers and COX-deficient fibers, along with decreased activity of respiratory chain complex IV. The variant was present at 81% in muscle and undetectable in fibroblasts and skin. While the variant was absent in blood from his mother and brother, it was also undetectable in the proband’s blood, therefore it is unclear if this was a de novo variant. There are no large families reported in the medical literature to consider for evidence of segregation. Of note, there is another individual reported with MELAS and this variant, however insufficient clinical details were provided to include this case for consideration for this variant curation (PMID: 20064630). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (81st percentile) as does HmtVar with a score of 0.7 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of heteroplasmy in COX-negative fibers (mean 99.3% and ranging from 98.8-99.7%, n=13) than in COX-positive fibers (mean 70.5% and ranging from 46.5-94.5%, n=11; p=0.002; PMID: 11335700; PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PS3_supporting.

Met criteria codes

• PS3_Supporting: Single fiber testing showed higher levels of heteroplasmy in COX-negative fibers (mean 99.3% and ranging from 98.8-99.7%, n=13) than in COX-positive fibers (mean 70.5% and ranging from 46.5-94.5%, n=11; p=0.002; PMID: 11335700; PS3_supporting).
• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
• PP3: The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (81st percentile) as does HmtVar with a score of 0.7 (PP3).

Not Met criteria codes

• PM6: While the variant was absent in blood from his mother and brother, it was also undetectable in the proband’s blood, therefore it is unclear if this was a de novo variant.
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: The m.4332G>A variant in MT-TQ has been reported in one individual from one family to date (PMID: 11171912), in a man with an atypical presentation of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). This individual had hearing loss beginning in his 20s and a stroke-like episode in his 40s. Muscle biopsy showed ragged red fibers and COX-deficient fibers, along with decreased activity of respiratory chain complex IV. The variant was present at 81% in muscle and undetectable in fibroblasts and skin. Of note, there is another individual reported with MELAS and this variant, however insufficient clinical details were provided to include this case for consideration for this variant curation (PMID: 20064630).
• PS2: While the variant was absent in blood from his mother and brother, it was also undetectable in the proband’s blood, therefore it is unclear if this was a de novo variant.
• PP1: There are no large families reported in the medical literature to consider for evidence of segregation.