Variant: NC_012920.1(MT-CYB):m.12217A>G

CA913169746

690161 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: f4c2d177-894b-42e8-8d92-15b6f73c2aa1

HGVS expressions

NC_012920.1:m.12217A>G
J01415.2:m.12217A>G

Uncertain Significance

• Met criteria codes: BP4

• Not Met criteria codes: PS3 PS4 BA1 PM2 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.12217A>G variant in MT-TS2 was reviewed by the Mitochondrial Disease Variant Curation Expert Panel on August 22, 2023. This variant has not been reported in the medical literature as causative in affected individuals or families with primary mitochondrial disease to our knowledge. There are several occurrences in population databases. The frequency in the MITOMAP GenBank sequences is 12/61,168 (0.020%). The frequency in the Helix dataset is 186/195,983 (0.095%) homoplasmic occurrences in addition to six heteroplasmic occurrences. The frequency in gnomAD v3.1.2 is 35/56,434 (0.062%). In all three population databases, this variant is seen in individuals from different haplogroups. MitoTIP suggests this variant is benign (5.8th percentile; BP4). There are no cybrids, single fiber studies, or other functional assays 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. We note that three experts on this panel felt likely benign was a more appropriate classification given the frequency in the general population and poor conservation at this site however the majority (four) agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4.

Met criteria codes

• BP4: MitoTIP suggests this variant is benign (5.8th percentile; BP4).

Not Met criteria codes

• PS3: There are no cybrids, single fiber studies, or other functional assays reported on this variant.
• PS4: This variant has not been reported in the medical literature as causative in affected individuals or families with primary mitochondrial disease to our knowledge.
• BA1: There are several occurrences in population databases. The frequency in the MITOMAP GenBank sequences is 12/61,168 (0.020%). The frequency in the Helix dataset is 186/195,983 (0.095%) homoplasmic occurrences in addition to six heteroplasmic occurrences. The frequency in gnomAD v3.1.2 is 35/56,434 (0.062%). In all three population databases, this variant is seen in individuals from different haplogroups.
• PM2: There are several occurrences in population databases. The frequency in the MITOMAP GenBank sequences is 12/61,168 (0.020%). The frequency in the Helix dataset is 186/195,983 (0.095%) homoplasmic occurrences in addition to six heteroplasmic occurrences. The frequency in gnomAD v3.1.2 is 35/56,434 (0.062%). In all three population databases, this variant is seen in individuals from different haplogroups.
• BS1: There are several occurrences in population databases. The frequency in the MITOMAP GenBank sequences is 12/61,168 (0.020%). The frequency in the Helix dataset is 186/195,983 (0.095%) homoplasmic occurrences in addition to six heteroplasmic occurrences. The frequency in gnomAD v3.1.2 is 35/56,434 (0.062%). In all three population databases, this variant is seen in individuals from different haplogroups.

Approved on: 2023-08-22

Published on: 2024-03-20