Variant: m.3946G>A

CA254862

9734 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 473be74e-f6c0-431a-8678-8699cc7fb752

Approved on: 2023-08-22

Published on: 2024-11-25

HGVS expressions

NC_012920.1:m.3946G>A
J01415.2:m.3946G>A
ENST00000361390.2:c.640G>A

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP4 PP3 PS4_Moderate PS3_Supporting

• Not Met criteria codes: BP4 PS1 PP1 PM6 PM5 BA1 BS1

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.3946G>A (p.E214K) variant in MT-ND1 has been reported in at least five unrelated individuals with features of a primary mitochondrial disease. Affected individuals had variable ages of onset (first few months of life to mid-teenage years). Features were variable but consistent with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), complex seizure disorder, or Leigh syndrome. Heteroplasmy ranged from 45% to 66% in fibroblasts or muscle (PS4_moderate; PMIDs: 26741492, 15466014, 31996177, 24105702). The variant was not detected in the blood or urine sediment of the mother in one case, however these tissues differed from that tested in the proband (PMID: 24105702). Electron transport chain (ETC) enzyme activities were assessed in multiple unrelated affected individuals with non-diagnostic exome sequencing and chromosomal microarray. Two individuals had major combined complex deficiency (Pt619 and Pt640; PMID: 26741492). An additional individual had approximately 20% residual activity in fibroblasts compared to controls, a 40%–60% decrease in mature complex I levels, reduced levels of MT-ND1 protein, and normal MT-ND1 mRNA levels (PP4; PMID: 24105702). Studies in E. coli (PMID: 16849371) and cybrids (PMID: 15466014) support the functional impact of this variant, and independent studies showed independent deleterious effects of the variant (PS3_supporting). The m.3946G>A variant is present in Mitomap’s GenBank dataset at less than 1/50,000 or 0.002% (1/61,168 sequences, 0.00163%, haplogroup L0f). This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.66 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 August 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP4, PS3_supporting, PP3, PM2_supporting.

Met criteria codes

• PM2_Supporting: The m.3946G>A variant is present in Mitomap’s GenBank dataset at less than 1/50,000 or 0.002% (1/61,168 sequences, 0.00163%, haplogroup L0f). This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals.
• PP4: Electron transport chain (ETC) enzyme activities were assessed in multiple unrelated affected individuals with non-diagnostic exome sequencing and chromosomal microarray. Two individuals had major combined complex deficiency (Pt619 and Pt640; PMID: 26741492). An additional individual had approximately 20% residual activity in fibroblasts compared to controls, a 40%–60% decrease in mature complex I levels, reduced levels of MT-ND1 protein, and normal MT-ND1 mRNA levels (PMID: 24105702) (PP4).
• PP3: The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.66 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).
• PS4_Moderate: The m.3946G>A in MT-ND1 (p.E214K) has been reported in at least 5 unrelated individuals with features of a primary mitochondrial disease. Affected individuals had variable ages of onset (first few months of life to mid-teenage years). Features were variable but consistent with MELAS, mitochondrial cytopathy, complex seizure disorder, or Leigh syndrome. Heteroplasmy ranged from 45% to 66% in fibroblasts or muscle (PS4_moderate; PMIDs: 26741492, 15466014, 31996177, 24105702).
• PS3_Supporting: Studies in E. coli (PMID: 16849371) and hybrids (PMID: 15466014) support the functional impact of this variant and independent studies showed independent deleterious effects of the variant (PS3_supporting).

Not Met criteria codes

• BP4: 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
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: The variant was not detected in the blood or urine sediment of the mother in one case, however these tissues differed from that tested in the proband (PMID: 24105702).
• 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
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline