rs121434474

Variant names:

• chrM-12147-G-A
• rs121434474
• unassigned_transcript_4812:c.10G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM6 PS3_Supporting PP3 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120576/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNH unassigned_transcript_4812 missense
• Scores: Mitotip Pathogenic 19
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1 MERRF-MELAS-/-Encephalopathy
• Conservation: PhyloP100: 6.27
• Publications: 1 publications found

Genes affected

TRNH (HGNC:7487): (mitochondrially encoded tRNA histidine)

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

TRNL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))

TRNS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

TRNS2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387441.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TH	ENST00000387441.1	TSL:6	n.10G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-ND5	ENST00000361567.2	TSL:6	c.-190G>A		upstream_gene	N/A	ENSP00000354813.2	P03915
	MT-ND4	ENST00000361381.2	TSL:6	c.*10G>A		downstream_gene	N/A	ENSP00000354961.2	P03905

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MERRF-MELAS-/-Encephalopathy

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Mitochondrial disease (2)
1	-	-	MELAS syndrome (2)
1	-	-	MERRF/MELAS overlap syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	19
Hmtvar	Pathogenic	1.0
PhyloP100		6.3

Other links and lift over

dbSNP: rs121434474; hg19: chrM-12148;