Variant: NC_012920.1:m.3902_3908inv

CA082749

9731 (ClinVar)

Gene: MT-ND1

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: b04011ab-11a2-4533-99f7-2507ea2fd88b

Approved on: 2022-06-30

Published on: 2022-06-30

HGVS expressions

NC_012920.1:m.3902_3908inv
NC_012920.1:m.3902_3908delinsGCAAGGT
J01415.2:m.3902_3908delinsGCAAGGT
ENST00000361390.2:c.596_602delinsGCAAGGT

Likely Pathogenic

• Met criteria codes: PM6_Strong PS3_Moderate PS4_Moderate PM2_Supporting

• Not Met criteria codes: PS2 PP3 PP4 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.3902_3908inv (p.DLA199GKV) variant in MT-ND1 has been reported in four unrelated individuals in the literature with primary mitochondrial disease with a range of clinical features including myopathy, exercise intolerance, Leigh syndrome, cardiomyopathy, failure to thrive, lactic acidosis, nephropathy, sensorineural hearing loss, and diabetes mellitus (PS4_moderate; PMIDs: 10775530, 16492986, 27290639, 34135385). Additionally, this expert panel knew of one local family with an affected individual with this variant that the expert panel agreed to include. There are at least three de novo occurrences reported in the literature and this variant in the case reported by the expert panel member also occurred de novo (PM6_strong; PMIDs: 16492986, 10775530, 27290639). 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). E. coli models demonstrated two different functional defects, reduced complex activity and reduced proton translocation (PS3_moderate; PMIDs; 34135385, 35234296). There are no in silico predictors for this type of variant in mitochondrial DNA. 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 Mitochondrial Disease Variant Curation Expert Panel on May 9, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_strong, PM2_supporting, PS3_moderate.

Met criteria codes

• PM6_Strong: There are at least three de novo occurrences reported in the literature and this variant in the case reported by the expert panel member also occurred de novo (PM6_strong; PMIDs: 16492986, 10775530, 27290639).
• PS3_Moderate: E. coli models demonstrated two different functional defects, reduced complex activity and reduced proton translocation (PS3_moderate; PMIDs; 34135385, 35234296). [Two E.coli model papers (Nuber 2021 PMID 34135385 & Hoeser 2022 PMID 352342960; Hoeser paper is especially strong since it showed no CI activity with triple AA mutant. The triple mutant model also demonstrated reduced proton translocation.]
• PS4_Moderate: The m.3902_3908inv (p.DLA199GKV) variant in MT-ND1 has been reported in four unrelated individuals in the literature with primary mitochondrial disease with a range of clinical features including myopathy, exercise intolerance, Leigh syndrome, cardiomyopathy, failure to thrive, lactic acidosis, nephropathy, sensorineural hearing loss, and diabetes mellitus (PS4_moderate; PMIDs: 10775530, 16492986, 27290639, 34135385). Additionally, this expert panel knew of one local family with an affected individual with this variant that the expert panel agreed to include. [4 unrelated patients in literature + 1 private patient submitted to the VCEP. The cases in the literature had an assortment of symptoms: mitochondrial myopathy, exercise intolerance; LS, cardiomyopathy, failure to thrive, lactic acidosis; nephropathy, deafness and diabetes mellitus. The private patient had spasm, seizure- like episodes, cognitive impairment, muscle weakness, abnormal EEG, elevated lactate in blood. Brain MRI showed unilateral abnormal lesions in temporal and occipital lobes.]
• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).

Not Met criteria codes

• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: There are no in silico predictors for this type of variant in mitochondrial DNA.
• PP4: Musemeci 2000 PMID 10775530 found isolated Complex I deficiency (~40% of normal) in muscle with ragged red fibers, but did not rule out other possible genetic causes.
• PP1: There are no large families reported in the medical literature to consider for evidence of segregation.