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.3697G>A") does not appear to be in HGVS format
  • See Evidence submitted by expert panel for details.

Variant: m.3697G>A

CA120647

9733 (ClinVar)

Gene: MT-ND1
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
Link to MONDO
UUID: 92937acb-7e51-46ae-82f7-7a511b084dab

HGVS expressions

NC_012920.1:m.3697G>A
J01415.2:m.3697G>A
ENST00000361390.2:n.391G>A

Likely Pathogenic

Met criteria codes 4
PS3_Supporting PS4_Moderate PM2_Supporting PP1_Moderate
Not Met criteria codes 7
BP4 PS2 PS1 PM4 PM5 PM6 PVS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
The m.3697G>A (p.G131S) variant in MT-ND1 has been reported in at least 14 individuals with primary mitochondrial disease from 8 families. Affected individuals had onset ranging from the first week of life to adulthood; and with features variably consistent with Leigh syndrome, MELAS, and LHON (PS4_moderate; PMIDs: 31996177, 30623604, 28429146, 24830958, 18977334, 17562939, 15466014). There are no reports of de novo occurrence of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 24830958, 17562939, 16969869, 15466014). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Functional studies supported the deleterious impact of this variant (PS3_supporting; PMID: 15466014). 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 March 22, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4_moderate, PM2_supporting, PP1_moderate.
Met criteria codes
PS3_Supporting
Functional studies supported the deleterious impact of this variant. The patient fibroblast cell line had complex I deficiency, hybrid cells (patient cells fused with rho0 cells) did not restore complex I activity although when fused with cells from an individual with an nDNA etiology, complex I activity was restored.
Tentative PubMed:15466014
PS4_Moderate
The m.3697G>A (p.G131S) variant in MT-ND1 has been reported in 7 individuals with primary mitochondrial disease with onset ranging from the first week of life to adulthood; and who had features variably consistent with Leigh syndrome, MELAS, and LHON (PS4_moderate; PMIDs: 31996177, 30623604, 28429146, 24830958, 18977334, 17562939, 15466014).
PM2_Supporting
This variant is absent in the GenBank data set, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
PP1_Moderate
This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 24830958, 17562939, 16969869, 15466014).
Not Met criteria codes
BP4
In silico tools (APOGEE) predict this variant to be neutral (0.36; BP4).
PS2
Per our literature review, there are no reported de novo occurrences of this variant.
PS1
There are no other pathogenic variants at this amino acid.
PM4
This variant does not result in a protein length change.
PM5
There are no other pathogenic variants at this amino acid.
PM6
Per our literature review, there are no reported de novo occurrences of this variant.
PVS1
This is not a deletion, nonsense, or frameshift variant.
Approved on: 2022-03-24
Published on: 2022-03-24
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