Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: m.14709T>C

CA120580

9617 (ClinVar)

Gene: MT-TE

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

Link to MONDO

UUID: 37b955f3-e355-4291-8257-71226d41ce0f

HGVS expressions

NC_012920.1:m.14709T>C

J01415.2:m.14709T>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PM2_Supporting PS3_Supporting PP1_Moderate PP3 PS4

PM6 PS2

Evidence Links 4

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.14709T>C variant in MT-TE has been reported in at least 39 affected individuals from 20 kindreds (PMIDs: 7726155, 7726154, 9353617, 10392369, 11437868, 15048886, 15880407, 15607216, 17161635, 17891417, 20045353, 26469001, 26885883, 29941710, 32313153, 33304817, 32948797; web story: https://www.chop.edu/stories/mitochondrial-disease-noras-story; PS4). Age of onset ranged from shortly after birth to 50s, although there are some reports of decreased fetal movements and hydrops fetalis. Features in affected individuals include myopathy, diabetes, pulmonary hypertension, ataxia, neuropathy, global developmental delay, dysarthria, hearing loss, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Furthermore, this variant has been reported in some individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh syndrome spectrum overlap and myoclonic epilepsy with ragged red fibers (MERRF). Muscle biopsies in affected individuals showed ragged red fibers, COX deficiency, and reduced respiratory chain enzyme activities. The variant was present at variable levels in affected and unaffected individuals. Some healthy family members had the variant present at homoplasmy, however heteroplasmy levels were generally higher in more severely affected individuals. The variant was present at 78% to homoplasmy in muscle and was variable among tissues from the same individual. There are no reported de novo occurrences to our knowledge. The variant segregates with manifestations in several families (PMIDs: 7726155, 7726154, 9353617, 10392369, 11437868, 15607216, 17161635, 17891417, 20045353; PP1_moderate). The computational predictor MitoTIP suggests this variant is pathogenic (56.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.9 (PP3). There is one occurrence in the GenBank population database, and the variant is absent in the Helix dataset and gnomAD v.3.1.2. Although there is one occurrence, the frequency is still low (PM2_supporting). Single fiber testing showed higher levels of heteroplasmy in COX-negative fibers (97.4 ± 3.5%; n=16) than in COX-positive fibers (89.6 ± 9.3%; n=15; P<0.004; PMID: 7726154), and cybrid studies, Northern blot analyses, and protein synthesis assays further support the functional impact of this variant (PMIDs: 15048886, 7726155, 12393175; PS3_supporting). 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 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_supporting.

PM2_Supporting

There is one occurrence in the GenBank population database, and the variant is absent in the Helix dataset and gnomAD v.3.1.2. Although there is one occurrence, the frequency is still low (PM2_supporting).

PS3_Supporting

Single fiber testing showed higher levels of heteroplasmy in COX-negative fibers (97.4 ± 3.5%; n=16) than in COX-positive fibers (89.6 ± 9.3%; n=15; P<0.004; PMID: 7726154), and cybrid studies, Northern blot analyses, and protein synthesis assays further support the functional impact of this variant (PMIDs: 15048886, 7726155, 12393175; PS3_supporting).

Single fiber testing showed higher levels of heteroplasmy in COX-negative fibers (97.4 ± 3.5%; n=16) than in COX-positive fibers (89.6 ± 9.3%; n=15; P<0.004; PMID: 7726154). PubMed:7726154

Mitochondrial translation products in fibroblasts from affected individuals did not differ qualitatively or quantitatively from those in control cultures. In myoblasts from one affected individual, densitometry indicated a 35% reduction in the rate of total translation, compared with that in control cultures. PubMed:7726155

Northern blot analysis showed reduction in steady state levels of mt-tRNAGlu in one individual, most obviously in fibroblasts (15% controls) and skeletal muscle (9%) controls. Steady state levels in cardiac tissue (tRNAs extracted from a gross tissue specimen) also were reduced, but less markedly to approximately 60% of that found in control tissue. Steady state levels of mt-tRNALeu[UUR] were normal in all of the tissues examined from an affected individual, indicating that the defect is specific to mt-tRNAGlu. In fibroblasts, an overall reduction in protein synthesis compared with controls was seen. There was no evidence of a specific decrease in the synthesis rate of any one particular protein subunit. PubMed:15048886

Cybrids were generated from proband in Vialettes et al., 1997 and rho0 cells (143B.TK- cell line). Fibroblasts had 71% heteroplasmy and fibroblast respiratory chain enzyme activities were as follows; complex I activity - 57% controls; complex IV activity - 72% controls. Cybrids with varying heteroplasmy levels were generated (11 clones had 4-95% heteroplasmy, 9 homoplasmic mutant, 7 homoplasmic WT), and homoplasmic mutant clones compared to homoplasmic wild type clones. There was no significant differences in the enzymatic activities between homoplasmic mutant cells and homoplasmic wild-type cybrid clones. On Northern blotting, tRNAGlu did not show any obvious size change in the mutant form compared to control, however there was a decrease in the quantity of the mature tRNAGlu transcripts in two of the three mutant clones to about 50% of the amount present in the wild-type clones. PubMed:12393175

PP1_Moderate

The variant segregates with manifestations in several families (PMIDs: 7726155, 7726154, 9353617, 10392369, 11437868, 15607216, 17161635, 17891417, 20045353; PP1_moderate).

PP3

The computational predictor MitoTIP suggests this variant is pathogenic (56.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.9 (PP3).

PS4

PM6

There are no reported de novo occurrences to our knowledge.

PS2

There are no reported de novo occurrences to our knowledge.

Approved on: 2023-01-23

Published on: 2023-03-15

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