rs118192100

Variant names:

• chrM-8363-G-A
• rs118192100
• unassigned_transcript_4803:c.69G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4_Moderate PP1_Moderate PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.8363G>A variant in MT-TK has been reported in at least 30 individuals with primary mitochondrial disease from 12 kindreds. Features seen in affected individuals include Leigh syndrome and myoclonic epilepsy with ragged red fibers (MERRF), as well as myopathy, peripheral neuropathy, ataxia, cardiomyopathy, sensorineural hearing loss, ophthalmoplegia, and lipomas. Heteroplasmy levels of this variant in affected individuals is variable, ranging from 40-97% (PS4_moderate; PMIDs: 8651277, 9052804, 10868777, 11108511, 19278689, 18319067, 19370763, 10102446, 16326995, 9932960). This variant segregated with disease in multiple affected family members in multiple families and several healthy family members had lower to undetectable levels (PP1_moderate; PMIDs: 9052804, 10868777, 10102446, 9932960). There are no confirmed de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 94.3 percentile, as does HmtVar with a score of 0.75 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing and cybrid analysis further support the functional impact of this variant (PS3_suporting). Single fiber testing showed the variant was significantly higher in COX-negative ragged red fibers (n = 5; 97.3% ± 2.5) than in normal fibers (n = 5; 89.2 ± 8.3; p < 0.05; PMID:9932960). Cybrid studies showed that clones with the variant present at homoplasmy had statistically significant decreases in Complex I, ATP synthase, and oxygen consumption (PMIDs: 15554876, 25909222). 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 March 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PP3, PP1_moderate, PS3_supporting, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120555/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNK unassigned_transcript_4803 splice_region, synonymous
• Scores: Mitotip Pathogenic 19
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:2 MICM+DEAF-/-MERRF-/-Autism-/-Leigh-Syndrome-/-Ataxia
• Conservation: PhyloP100: 5.17
• Publications: 2 publications found

Genes affected

TRNK (HGNC:7489): (mitochondrially encoded tRNA lysine)

MT-ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

MT-ATP8 (HGNC:7415): (mitochondrially encoded ATP synthase 8) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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.
• PP1: 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: ENST00000387421.1. 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-TK	ENST00000387421.1	TSL:6	n.69G>A		splice_region non_coding_transcript_exon	Exon 1 of 1
	MT-ATP6	ENST00000361899.2	TSL:6	c.-164G>A		upstream_gene	N/A	ENSP00000354632.2
	MT-ATP8	ENST00000361851.1	TSL:6	c.-3G>A		upstream_gene	N/A	ENSP00000355265.1

Frequencies

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

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56434

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56434

Mitomap

Disease(s): MICM+DEAF-/-MERRF-/-Autism-/-Leigh-Syndrome-/-Ataxia

Status: Cfrm-[LP]

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	MELAS syndrome (2)
1	-	-	Cardiomyopathy and Deafness (1)
1	-	-	Mitochondrial disease (1)
-	-	-	Leigh syndrome (1)
-	-	-	MERRF syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	19
Hmtvar	Pathogenic	0.75
PhyloP100		5.2

Other links and lift over

dbSNP: rs118192100; hg19: chrM-8364;