Variant: NC_012920.1(MT-ND6):m.14633A>G

Version: 1.1
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CA414823366

618219 (ClinVar)

Gene: MT-TN (HGNC:4570)

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: e0804895-ec82-4adb-89f4-3974966b66c5

Approved on: 2023-03-28

Published on: 2023-03-29

HGVS expressions

NC_012920.1:m.14633A>G
J01415.2:m.14633A>G
ENST00000361681.2:c.41T>C

Uncertain Significance

• Met criteria codes: BP4

• Not Met criteria codes: PS3 PS2 PS4 PP3 PP1 PM2 PM6 BA1 BS3 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.14633A>G (p.M14T) variant in MT-ND6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on March 28, 2023. There are no individuals or families with this variant reported in the medical literature to our knowledge. There are several occurrences in population databases. This variant is absent in GenBank MITOMAP sequences. It is present in 0.005% of individuals in gnomAD v3.1.2 (two homoplasmic occurrences in individuals of European background and haplogroup HV; one homoplasmic occurrence in an individual of African/African American background and haplogroup L3) and in 0.005% of individuals in the Helix dataset (10 homoplasmic occurrences and two heteroplasmic occurrences). In silico tools (APOGEE) predict this variant to be neutral (score of 0.4, BP4). There are no cybrid, single fiber, or other studies 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 March 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4.

Met criteria codes

• BP4: In silico tools (APOGEE) predict this variant to be neutral (score of 0.4, BP4).

Not Met criteria codes

• PS3: There are no cybrid, single fiber, or other studies reported for this variant.
• PS2: There are no individuals or families with this variant reported in the medical literature to our knowledge.
• PS4: There are no individuals or families with this variant reported in the medical literature to our knowledge.
• PP3: In silico tools (APOGEE) predict this variant to be neutral (score of 0.4, BP4).
• PP1: There are no individuals or families with this variant reported in the medical literature to our knowledge.
• PM2: There are several occurrences in population databases. This variant is absent in GenBank MITOMAP sequences. It is present in 0.005% of individuals in gnomAD v3.1.2 (two homoplasmic occurrences in individuals of European background and haplogroup HV; one homoplasmic occurrence in an individual of African/African American background and haplogroup L3) and in 0.005% of individuals in the Helix dataset (10 homoplasmic occurrences and two heteroplasmic occurrences).
• PM6: There are no individuals or families with this variant reported in the medical literature to our knowledge.
• BA1: There are several occurrences in population databases. This variant is absent in GenBank MITOMAP sequences. It is present in 0.005% of individuals in gnomAD v3.1.2 (two homoplasmic occurrences in individuals of European background and haplogroup HV; one homoplasmic occurrence in an individual of African/African American background and haplogroup L3) and in 0.005% of individuals in the Helix dataset (10 homoplasmic occurrences and two heteroplasmic occurrences).
• BS3: There are no cybrid, single fiber, or other studies reported for this variant.
• BS1: There are several occurrences in population databases. This variant is absent in GenBank MITOMAP sequences. It is present in 0.005% of individuals in gnomAD v3.1.2 (two homoplasmic occurrences in individuals of European background and haplogroup HV; one homoplasmic occurrence in an individual of African/African American background and haplogroup L3) and in 0.005% of individuals in the Helix dataset (10 homoplasmic occurrences and two heteroplasmic occurrences).