Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document
  • There was no gene found in the curated document received from the VCI/VCEP
  • Gene listed was thus derived from ClinVar and/or CAR
  • The variant label for this record ("m.3376G>A") does not appear to be in HGVS format
  • No CSPEC related information was provided by the message!
  • See Evidence submitted by expert panel for details.

Variant: m.3376G>A

CA345259

65921 (ClinVar)

Gene: MT-ND1
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
Link to MONDO
UUID: 9eb2ff48-bac5-47e1-a1f0-56a2b5d15bc4

HGVS expressions

NC_012920.1:m.3376G>A
J01415.2:m.3376G>A
ENST00000361390.2:n.70G>A

Uncertain Significance

Met criteria codes 3
BP4 PS2_Supporting PM2_Supporting
Not Met criteria codes 5
PS4 PS3 PP1 PP4 PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
The m.3376G>A (p.E24K) variant in MT-ND1 has been reported in one individual to date with primary mitochondrial disease. This individual had features in the MELAS/LHON spectrums and harbored the variant at 98% heteroplasmy in muscle, 18% in blood, and 67% in urine. This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals. This variant was de novo in the single reported case, as the proband's mother and siblings did not have the variant in blood or urine via PCR-RFLP (PS2_supporting; PMID: 15657614). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of neutral with a borderline pathogenicity predictor score, 0.5 (Min=0, Max=1), evidence that does not predict a damaging effect on gene function (BP4). There are no cybrids or single fiber studies reported on this variant. 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 Mitochondrial Disease Variant Curation Expert Panel on February 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria (PMID: 32906214): PS2_supporting, PM2_supporting, BP4.
Met criteria codes
BP4
The computational predictor APOGEE gives a consensus rating of neutral with a borderline pathogenicity predictor score, 0.5 (Min=0, Max=1), evidence that does not predict a damaging effect on gene function (BP4).
PS2_Supporting
This variant was de novo in the single reported case, as the proband's mother and siblings did not have the variant in blood or urine via PCR-RFLP (PS2_supporting; PMID: 15657614). Maternity confirmed as mother also harbored another predicated benign variant in the mitochondrial genome m.3865 A>G at homoplasmic level similar to the proband.
PM2_Supporting
This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
Not Met criteria codes
PS4
This variant has been reported in one individual to date with primary mitochondrial disease. This individual had features in the MELAS/LHON spectrums and harbored the variant at 98% heteroplasmy in muscle, 18% in blood, and 67% in urine. This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals.
PS3
There are no cybrids or single fiber studies reported on this variant. PMID:15657614 Presented e. coli with the variant equivalent to them m.3376G>A substitution associated with LHON/MELAS overlap syndrome produces a biochemical defect of similar magnitude to that commonly observed with MELAS mutations. Three-to-four-fold increased apparent Km for ubiquinones in the NuoH-E36Q mutant and resistance to the type A inhibitors piericidin A and annonins, which bind at or near the UQ binding domain, suggest that also NuoH-E36K interferes with UQ binding. Note the bacteria was homoplasmic and the reported case was heteroplasmic.
PP1
There are no large families reported in the medical literature to consider for evidence of segregation.
PP4
Other causes were not excluded only mitochondrial genome performed. Muscle testing noted complex I activity 36% compared to controls and I/II at 40%.
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2022-06-30
Published on: 2022-06-30
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