Variant: NC_012920.1:m.10254G>A

CA345916

155887 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 43500f02-a096-4480-b958-ed35d5394a80

Approved on: 2023-10-23

Published on: 2024-11-25

HGVS expressions

NC_012920.1:m.10254G>A
J01415.2:m.10254G>A
ENST00000361227.2:c.196G>A

Likely Pathogenic

• Met criteria codes: PS4_Moderate PP3 PM2_Supporting PM6

• Not Met criteria codes: BS1 PS3 PS1 PP4 PM5 BA1

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.10254G>A (p.D66N) variant in MT-ND3 has been reported in at least five unrelated individuals with primary mitochondrial disease. Three individuals had features consistent with Leigh syndrome, with onset in or around the first year of life, and two individuals had features of optic neuropathy (PS4_moderate; PMIDs: 20202874, 27290639, 26238931, 36913248). There are at least two de novo occurrences reported in the literature (PM6; PMIDs: 20202874, 27290639). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic with raw scores of 0.56 and 0.925, respectively (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic 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 October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6, PM2_supporting, PP3.

Met criteria codes

• PS4_Moderate: The m.10254G>A (p.D66N) variant in MT-ND3 has been reported in at least 5 unrelated individuals with primary mitochondrial disease. Three individuals had features consistent with Leigh syndrome, with onset in or around the first year of life, and two individuals had features of hereditary optic neuropathy (PS4_moderate; PMIDs: 20202874, 27290639, 26238931, 36913248).
• PP3: The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic with raw scores of 0.56 and 0.925, respectively (Min=0, Max=1), which predict a damaging effect on gene function (PP3).
• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
• PM6: There are at least two de novo occurrences reported in the literature (PM6_moderate; PMIDs: 20202874, 27290639).

Not Met criteria codes

• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: While nuclear causes of disease were excluded in one proband (PMID:27290639) and biochemical deficiency was shown in another individual (PMID:20202874), there were no cases where nuclear causes of disease and biochemical deficiencies were thoroughly evaluated in the same individual (PP4_not met).
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline