Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document
  • There was no gene found in the curated document received from the VCI/VCEP
  • Gene listed was thus derived from ClinVar and/or CAR
  • The variant label for this record ("m.12147G>A") does not appear to be in HGVS format

Variant: m.12147G>A

CA120576

9610 (ClinVar)

Gene: MT-TH
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
Link to MONDO
UUID: 76c21ebb-4a23-458c-a7d2-738c4df20b87

HGVS expressions

NC_012920.1:m.12147G>A
J01415.2:m.12147G>A

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 5
PM2_Supporting PS4_Supporting PP3 PS3_Supporting PM6
Not Met criteria codes 1
PS2

Evidence Links 2

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.12147G>A variant in MT-TH has been reported in two unrelated probands with features of primary mitochondrial disease. Both individuals were males with symptom onset in late teens to early 20s, developed seizures, and had COX-negative fibers identified on muscle biopsy. One individual also had ragged red fibers, and complex I and IV deficiencies. Additional features seen include sensorineural hearing loss, optic atrophy, ptosis, migraines, ataxia, myoclonus, muscle weakness, hepatic failure consistent with Reye syndrome, lactic acidosis, and hyperCKemia. Heteroplasmy in the affected individuals ranged from 86% in muscle to undetectable in hair (PS4_supporting; PMIDs: 14967777, 15111688). This variant occurred de novo in one individual (absent in blood, urine, hair, and muscle from mother as well as two sisters, two maternal aunts, and two maternal uncles; PM6, PMID: 15111688). The computational predictor MitoTIP suggests this variant is pathogenic (93.5 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing was performed in muscle fibers from both affected individuals, supporting the functional impact of this variant (PS3_supporting). In one individual, the mean heteroplasmy level in abnormal fibers was 90% ± 2% (n=22) and in normal fibers was 58% ± 6% (n=15; P = 0.007). Furthermore, in ragged red fibers, the mean heteroplasmy level was 94% (PMID: 14967777). In the other individual, the mean heteroplasmy level in COX-deficient fibers was 94.6 ± 1.53% (n = 12) and in COX-positive fibers was 32.5 ± 6.18% (n = 10; p < 0.0001; PMID: 15111688). 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 January 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM6, PM2_supporting, PP3, PS3_supporting.
Met criteria codes
PM2_Supporting
This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
PS4_Supporting
The m.12147G>A variant in MT-TH has been reported in two unrelated probands with features of primary mitochondrial disease. Both individuals were males with symptom onset in late teens to early 20s, developed seizures, and had COX-negative fibers identified on muscle biopsy. One individual also had ragged red fibers, and complex I and IV deficiencies. Additional features seen include sensorineural hearing loss, optic atrophy, ptosis, migraines, ataxia, myoclonus, muscle weakness, hepatic failure consistent with Reye syndrome, lactic acidosis, and hyperCKemia. Heteroplasmy in the affected individuals ranged from 86% in muscle to undetectable in hair (PS4_supporting; PMIDs: 14967777, 15111688).
PP3
The computational predictor MitoTIP suggests this variant is pathogenic (93.5 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3).
PS3_Supporting
Single fiber testing was performed in muscle fibers from both affected individuals, supporting the functional impact of this variant (PS3_supporting). In one individual, the mean heteroplasmy level in abnormal fibers was 90% ± 2% (n=22) and in normal fibers was 58% ± 6% (n=15; P = 0.007). Furthermore, in ragged red fibers, the mean heteroplasmy level was 94% (PMID: 14967777). In the other individual, the mean heteroplasmy level in COX-deficient fibers was 94.6 ± 1.53% (n = 12) and in COX-positive fibers was 32.5 ± 6.18% (n = 10; p < 0.0001; PMID: 15111688).
COX negative fibers (94.6%) than in COX positive fibers (32.5%), p < 0.0001 PubMed:15111688
COX negative fibers (90%) than in COX positive fibers (58%), p= 0.007 PubMed:14967777
PM6
This variant occurred de novo in one individual (absent in blood, urine, hair, and muscle from mother as well as two sisters, two maternal aunts, and two maternal uncles; PM6, PMID: 15111688).
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-01-09
Published on: 2023-03-14
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