The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • There was no gene found in the curated document received from the VCI/VCEP
  • The variant label for this record ("m.12207G>A") does not appear to be in HGVS format
  • Despite there being a valid 'cspec' property in the messages there's a discrepancy in message contents and CSPEC data: * Message Gene: undefined CSPEC Genes: [] * Message MONDOs: MONDO:0044970 CSPEC MONDO: []
  • No CSPEC computed assertion could be determined for this classification!


Variant: m.12207G>A

CA120545

9561 (ClinVar)

Gene: N/A
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
UUID: e7fc8c03-93ee-454b-a8df-5f6719c13472
Approved on: 2024-05-13
Published on: 2024-11-26

HGVS expressions

NC_012920.1:m.12207G>A
J01415.2:m.12207G>A

Uncertain Significance

Met criteria codes 3
PS4_Supporting PP3 PM2_Supporting
Not Met criteria codes 3
PM1 PS3 PP1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
The m.12207G>A variant in MT-TS2 has been reported in three individuals with primary mitochondrial disease to date. One person had clinical features consistent with myoclonic epilepsy with ragged red fibers (MERRF) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS; PMID: 16950817), had complex I deficiency in muscle, and had the variant present at 92% heteroplasmy in muscle. The variant was undetectable in the mother’s blood. Another individual was reported as part of a primary mitochondrial disease cohort (PMID: 27450679) and was found to have the variant present at >60% in muscle and was undetectable in blood from the proband and mother. The variant was also seen in a Japanese family with diabetes, epilepsy, deafness, and developmental delay. The variant was found in the proband at 31.3% heteroplasmy in blood, 52.6% in saliva, and 73.9% in urinary sediment while the variant was found in the mother at 13.8%, 22.1%, and 29.4%, respectively (PMID: 36967720; PS4_supporting). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is deleterious (76.4 percentile) and HmtVAR predicts it to be deleterious with a score of 0.5 (PP3). 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. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP3, PM2_supporting.
Met criteria codes
PS4_Supporting
The m.12207G>A variant in MT-TS2 has been reported in three individuals with primary mitochondrial disease to date. One person had clinical features consistent with myoclonic epilepsy with ragged red fibers (MERRF) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS; PMID 16950817), had complex I deficiency in muscle, and had the variant present at 92% heteroplasmy in muscle. The variant was undetectable in the mother’s blood. Another individual was reported as part of a primary mitochondrial disease cohort (PMID 27450679) and was found to have the variant present at >60% in muscle and was undetectable in blood from the proband and mother. The variant was also seen in a Japanese family with diabetes, epilepsy, deafness, and developmental delay. The variant was found in the proband at 31.3% heteroplasmy in blood, 52.6% in saliva, and 73.9% in urinary sediment while the variant was found in the mother at 13.8%, 22.1%, and 29.4%, respectively (PMID 36967720; PS4_supporting).
PP3
The computational predictor MitoTIP suggests this variant is deleterious (76.4 percentile) and HmtVAR predicts it to be deleterious with a score of 0.5 (PP3).
PM2_Supporting
This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
Not Met criteria codes
PM1
Variant m. 12207G>A was found at different levels of heteroplasmy. In case #1, it was heteroplasmic in patient muscle (92%) but was not found in the unaffected mother’s blood. In the case #2, it was >60% in patient muscle but absent in blood of both the patient and the mother. In the family of case #3, the variant was found in the patient at 31.3% (blood), 52.6% (saliva), and 73.9% (urinary sediments) while those of his mother were 13.8%, 22.1%, and 29.4%, respectively. No genetic testing was done of the lesser affected grandmother.
PS3
There are no cybrids, single fiber studies, or other functional assays reported on this variant.

PP1
Variant m. 12207G>A was found at different levels of heteroplasmy. In case #1, it was heteroplasmic in patient muscle (92%) but was not found in the unaffected mother’s blood. In the case #2, it was >60% in patient muscle but absent in blood of both the patient and the mother. In the family of case #3, the variant was found in the patient at 31.3% (blood), 52.6% (saliva), and 73.9% (urinary sediments) while those of his mother were 13.8%, 22.1%, and 29.4%, respectively. No genetic testing was done of the lesser affected grandmother.
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.