Variant: NC_012920.1(MT-ND1):m.4132G>A

CA16603348

377340 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 596d01da-b96d-4c92-856f-85c304278d0a

Approved on: 2023-05-23

Published on: 2025-06-03

HGVS expressions

NC_012920.1:m.4132G>A
J01415.2:m.4132G>A
ENST00000361390.2:c.826G>A

Uncertain Significance

• Met criteria codes: PP3

• Not Met criteria codes: PS2 PS3 PS4 PM6 PM2

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.4132G>A (p.A276T) variant in MT-ND1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on May 23, 2023. There is one family reported in the medical literature with this variant (PMID: 17454741). The six affected individuals in this family had non-arteritic anterior ischemic optic neuropathy. The variant was present at homoplasmy in all affected family members and information is not provided on testing status in unaffected family members, precluding consideration for segregation evidence. There are no other individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.015%, 9/61,883; gnomAD v3.1.2: 0.019%, 11/56,428 homoplasmic occurrences; Helix: 0.041%, 80/195,893 homoplasmic occurrences). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.58 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported for 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP3.

Met criteria codes

• PP3: The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.58 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).

Not Met criteria codes

• PS2: Details of testing of family members was not provided.
• PS3: There are no cybrids, single fiber studies, or other functional assays reported for this variant.
• PS4: There is one family reported in the medical literature with this variant (PMID: 17454741). The six affected individuals in this family had non-arteritic anterior ischemic optic neuropathy. The variant was present at homoplasmy in all affected family members.
• PM6: Details of testing of family members was not provided.
• PM2: This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.015%, 9/61,883; gnomAD v3.1.2: 0.019%, 11/56,428 homoplasmic occurrences; Helix: 0.041%, 80/195,893 homoplasmic occurrences).