Variant: NC_012920.1(MT-TL1):m.3243A>G

Version: 1.1
JSON-LD PDF

CA120560

9589 (ClinVar)

Gene: MT-TL1 (HGNC:4567)

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 9cb92cab-af79-45a9-8ce6-2337aca50924

Approved on: 2020-08-20

Published on: 2025-08-07

HGVS expressions

NC_012920.1:m.3243A>G
J01415.2:m.3243A>G

Pathogenic

• Met criteria codes: PP3 PP1_Moderate PM6_Strong PS4

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.3243A>G variant in MT-TL1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease (PS4; PMIDs: 1670860, 2102678, 2268345, 17823937, 23806424, 16682545, 18391161, 9323566, 18294221, 16717204, 12874464, 9285090, 11260383, 30133155, 9323566, 23360351, 10799437, 12221518, 29560378). Clinical syndromes seen in affected individuals include mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), chronic progressive external ophthalmoplegia (CPEO), and Leigh syndrome. Clinical features seen in affected individuals are variable and include myopathy, neuropathy, seizures, hemiparesis, stroke-like episodes, ataxia, dementia, developmental delay and/or regression, headache, migraine, short stature, diabetes, gastrointestinal involvement (dysmotility, reduced appetite, vomiting, dysphagia, constipation, diarrhea), ophthalmoplegia, optic atrophy, retinal dystrophy, ptosis, sensorineural hearing loss, cardiomyopathy, Wolff-Parkinson-White, renal involvement (tubulopathy, focal segmental glomerulosclerosis), mood disorder, lactic acidosis, and ragged red fibers on muscle biopsy. Age of onset ranges from early in life to adulthood. There are several reported de novo occurrences of this variant (PM6_strong; PMIDs: 27331024, 27450679, 11168879). Additionally, 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: 1539604, 8492919, 7931425, 1487758). There are several occurrences of this variant in population databases. The computational predictor MitoTIP suggests this variant is pathogenic (58.8 percentile) and HmtVAR predicts it to be pathogenic with a score of 1 (PP3). Cybrid and single fiber studies support the functional impact of this variant (PMIDs: 18455161, 1378759, 1732728, 8154867, 9741403). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a maternal manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6_strong, PP1_moderate, PP3.

Met criteria codes

• PP3: The computational predictor MitoTIP suggests this variant is pathogenic (58.8 percentile) and HmtVAR predicts it to be pathogenic with a score of 1 (PP3).
• PP1_Moderate: Additionally, 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: 1539604, 8492919, 1487758).
• PM6_Strong: There are several reported de novo occurrences of this variant (PM6_strong; PMIDs: 27331024, 27450679, 11168879).
• PS4: The m.3243A>G variant in MT-TL1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease (PS4; PMIDs: 1670860, 2102678, 2268345, 17823937, 23806424, 16682545, 18391161, 9323566, 18294221, 16717204, 12874464, 9285090, 11260383, 30133155, 9323566, 23360351, 10799437, 12221518, 29560378). Clinical syndromes seen in affected individuals include mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), chronic progressive external ophthalmoplegia (CPEO), and Leigh syndrome. Clinical features seen in affected individuals are variable and include myopathy, neuropathy, seizures, hemiparesis, stroke-like episodes, ataxia, dementia, developmental delay and/or regression, headache, migraine, short stature, diabetes, gastrointestinal involvement (dysmotility, reduced appetite, vomiting, dysphagia, constipation, diarrhea), ophthalmoplegia, optic atrophy, retinal dystrophy, ptosis, sensorineural hearing loss, cardiomyopathy, Wolff-Parkinson-White, renal involvement (tubulopathy, focal segmental glomerulosclerosis), mood disorder, lactic acidosis, and ragged red fibers on muscle biopsy. Age of onset ranges from early in life to adulthood.