Variant: NC_012920.1(MT-ND1):m.1624C>T

CA120537

9549 (ClinVar)

Gene: MT-TV

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 2c68f444-ee58-4395-8ed2-3a635660f219

Approved on: 2024-09-24

Published on: 2025-05-14

HGVS expressions

NC_012920.1:m.1624C>T
J01415.2:m.1624C>T

Likely Pathogenic

• Met criteria codes: PS3_Moderate PP3 PM2_Supporting PS4_Moderate

• Not Met criteria codes: PS2 PM6

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.1624C>T variant in MT-TV has been reported in two families with primary mitochondrial disease (PMIDs: 11799391, 23063709). The proband in the first family reported was a woman with migraines, muscle weakness, reduced COX activity on histochemistry in skeletal muscle, and reduced activities of complexes I and IV in skeletal muscle. The variant was present at homoplasmy in her blood and muscle sample. She had a son with Leigh syndrome with the variant present at homoplasmy in buccal sample. She had six other children who died in the first days of life due to lactic acidosis, including one child who also had severe cardiac failure and hypertrophic cardiomyopathy who was found to have the variant present at homoplasmy in blood, muscle, and cardiac tissue. She also had three siblings who died in early infancy (PMID: 11799391). The proband in the second family reported was a man with adult-onset Leigh syndrome. He presented at age 25 years with transient mild consciousness disturbance and agitation. By 29 years he had left ventricular hypertrophy, constricted visual fields, ataxic gait, slurred speech, and poor coordination. By his mid-30s, he has personality changes and cognitive decline. He had elevated blood and cerebrospinal fluid lactate levels. Brain imaging at ages 25 years and 35 years revealed mild frontal lobe atrophy and low and high signal intensity spots on T1- and T2-weighted images, respectively, in the right caudate head and bilateral putamen. The variant was present in muscle (89% at age 29 years, 60% at age 36 years) and blood (48% at 29 years, 34% at age 36 years). His mother had onset of stroke-like episodes in her mid-30s in addition to psychiatric involvement. She was noted to have left-sided paresis in her 40s. The variant was present in her blood at 17% (PMID: 23063709). Additionally, an Expert Panel member knew of an additional two cases (one baby, one adult) who were very ill and had the variant present at homoplasmy (PS4_moderate). There are no de novo occurrences of this variant reported to our knowledge. This variant is absent in MITOMAP. There are no homoplasmic occurrences in gnomAD v3.1.2 or the Helix dataset, however there is one heteroplasmic occurrence in gnomAD and two heteroplasmic occurrences in Helix. Although there are several heteroplasmic occurrences, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (68.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.45 (PP3). Strong cybrid studies and analysis in patient myoblasts and fibroblasts support the functional impact of this variant (PS3_moderate; PMID: 18400783). In summary, this variant meets criteria to be classified as likely pathogenic 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 September 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_moderate, PM2_supporting, PP3.

Met criteria codes

• PP3: The computational predictor MitoTIP suggests this variant is pathogenic (68.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.45 (PP3).
• PM2_Supporting: This variant is absent in MITOMAP. There are no homoplasmic occurrences in gnomAD v3.1.2 or the Helix dataset, however there is one heteroplasmic occurrence in gnomAD and two heteroplasmic occurrences in Helix. Although there are several heteroplasmic occurrences, the frequency is still low (PM2_supporting).
• PS4_Moderate: The m.1624C>T variant in MT-TV has been reported in two families with primary mitochondrial disease (PMIDs: 11799391, 23063709). The proband in the first family reported was a woman with migraines, muscle weakness, reduced COX activity on histochemistry in skeletal muscle, and reduced activities of complexes I and IV in skeletal muscle. The variant was present at homoplasmy in her blood and muscle sample. She had a son with Leigh syndrome with the variant present at homoplasmy in buccal sample. She had six other children who died in the first days of life due to lactic acidosis, including one child who also had severe cardiac failure and hypertrophic cardiomyopathy who was found to have the variant present at homoplasmy in blood, muscle, and cardiac tissue. She herself had three siblings who died in early infancy (PMID: 11799391). The proband in the second family was a man with adult-onset Leigh syndrome. He presented at age 25 years with transient mild consciousness disturbance and agitation. By 29 years he had left ventricular hypertrophy, constricted visual fields, ataxic gait, slurred speech, and poor coordination. By his mid-30s, he has personality changes and cognitive decline. He had elevated blood and cerebrospinal fluid lactate levels. Brain imaging at ages 25 years and 35 years revealed mild frontal lobe atrophy and low and high signal intensity spots on T1- and T2-weighted images, respectively, in the right caudate head and bilateral putamen. The variant was present in muscle (89% at age 29 years, 60% at age 36 years) and blood (48% at 29 years, 34% at age 36 years). His mother had onset of stroke-like episodes in her mid-30s in addition to psychiatric involvement. She was noted to have left-sided paresis in her 40s. The variant was present in her blood at 17% (PMID: 23063709). Additionally, an Expert Panel member knew of an additional two cases (one baby, one adult) who were very ill and had the variant present at homoplasmy (PS4_moderate).

Not Met criteria codes

• PS2: There are no de novo occurrences of this variant reported to our knowledge.
• PM6: There are no de novo occurrences of this variant reported to our knowledge.