rs199476130
Variant summary
Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PS4_ModeratePS3_SupportingPP3PM6_StrongPM2_Supporting
This summary comes from the ClinGen Evidence Repository: The m.5703G>A variant in MT-TN has been reported in four unrelated individuals with primary mitochondrial disease (PS4_moderate). These four individuals were from three different backgrounds including African American (one individual), Chinese (one individual), and Caucasian (two individuals, one from France and one from Spain). Features seen in affected individuals include myoclonic epilepsy with ragged red fibers (MERRF) and chronic progressive external ophthalmoplegia (CPEO), as well as exercise intolerance, severe underweight, and hearing loss (PMIDs: 8254046, 14518831, 30897601, 32419253). The variant in these four cases was seen at varying degrees of heteroplasmy in muscle (14-80%), blood (5-48%), urine (4-11%), and buccal (7-59%). The variant was reported to have arisen de novo in three of the four affected individuals (PM6_strong, PMIDs: 8254046, 30897601, 32419253) and no details about family member testing were provided for the other individual. Furthermore, the variant’s presence in individuals of different ethnic backgrounds was also considered as indirect evidence of a de novo occurrence at some time in the past. There are no other large families reported in the medical literature to consider for evidence of segregation. There is one occurrence of this variant in GenBank dataset and it is absent in gnomAD v3.1.2 and in the Helix dataset, therefore the overall frequency is still very low (PM2_supporting). The computational predictor MitoTIP predicts this variant to be pathogenic, scoring in the 89.9 percentile and HmtVAR also predicts it to be pathogenic with a score of 0.85 (PP3). Multiple independent studies support the functional impact of this variant (PS3_supporting). Single-fiber testing in two of the four affected individuals was performed and showed that the variant was present at higher heteroplasmy in COX-negative fibers than COX-positive fibers (93% heteroplasmy in COX-negative fibers compared to 2% in COX-positive fibers in one individual, P<.0001, PMID:32419253; and 97-100% in COX-negative fibers compared to 3-63% in COX-positive fibers in the other individual, PMID:8254046). Furthermore, cybrids with high levels of the variant demonstrated a severe mitochondrial protein synthesis defect and impaired oxidative phosphorylation (PMIDs: 8254046, 9372914). tRNA conformational studies showed impaired aminoacylation with severe reduction of the tRNA Asn pool (PMID:9372914). In summary, this variant meets criteria to be classified as likely pathogenic however, after extensive discussion, this Expert Panel elected to modify the classification to pathogenic given consistent functional evidence of severe deleterious effect across multiple independent studies and given repeated apparent de novo occurrences across individuals of different ethnic backgrounds. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PS3_supporting, PP3, PM2_supporting, PM6_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120583/MONDO:0044970/014
Frequency
Consequence
unassigned_transcript_4796 synonymous
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNN | unassigned_transcript_4796 | c.27C>T | p.Cys9Cys | synonymous_variant | Exon 1 of 1 | |||
| COX1 | unassigned_transcript_4799 | c.-201G>A | upstream_gene_variant | |||||
| TRNA | unassigned_transcript_4795 | c.-48C>T | upstream_gene_variant |
Ensembl
Frequencies
Mitomap
ClinVar
Submissions by phenotype
Ophthalmoplegia, isolated Pathogenic:1
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Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
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Mitochondrial disease Pathogenic:1
The m.5703G>A variant in MT-TN has been reported in four unrelated individuals with primary mitochondrial disease (PS4_moderate). These four individuals were from three different backgrounds including African American (one individual), Chinese (one individual), and Caucasian (two individuals, one from France and one from Spain). Features seen in affected individuals include myoclonic epilepsy with ragged red fibers (MERRF) and chronic progressive external ophthalmoplegia (CPEO), as well as exercise intolerance, severe underweight, and hearing loss (PMIDs: 8254046, 14518831, 30897601, 32419253). The variant in these four cases was seen at varying degrees of heteroplasmy in muscle (14-80%), blood (5-48%), urine (4-11%), and buccal (7-59%). The variant was reported to have arisen de novo in three of the four affected individuals (PM6_strong, PMIDs: 8254046, 30897601, 32419253) and no details about family member testing were provided for the other individual. Furthermore, the variant’s presence in individuals of different ethnic backgrounds was also considered as indirect evidence of a de novo occurrence at some time in the past. There are no other large families reported in the medical literature to consider for evidence of segregation. There is one occurrence of this variant in GenBank dataset and it is absent in gnomAD v3.1.2 and in the Helix dataset, therefore the overall frequency is still very low (PM2_supporting). The computational predictor MitoTIP predicts this variant to be pathogenic, scoring in the 89.9 percentile and HmtVAR also predicts it to be pathogenic with a score of 0.85 (PP3). Multiple independent studies support the functional impact of this variant (PS3_supporting). Single-fiber testing in two of the four affected individuals was performed and showed that the variant was present at higher heteroplasmy in COX-negative fibers than COX-positive fibers (93% heteroplasmy in COX-negative fibers compared to 2% in COX-positive fibers in one individual, P<.0001, PMID: 32419253; and 97-100% in COX-negative fibers compared to 3-63% in COX-positive fibers in the other individual, PMID: 8254046). Furthermore, cybrids with high levels of the variant demonstrated a severe mitochondrial protein synthesis defect and impaired oxidative phosphorylation (PMIDs: 8254046, 9372914). tRNA conformational studies showed impaired aminoacylation with severe reduction of the tRNA Asn pool (PMID: 9372914). In summary, this variant meets criteria to be classified as likely pathogenic however, after extensive discussion, this Expert Panel elected to modify the classification to pathogenic given consistent functional evidence of severe deleterious effect across multiple independent studies and given repeated apparent de novo occurrences across individuals of different ethnic backgrounds. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_supporting, PP3, PM2_supporting, PM6_strong. -
Computational scores
Source: