rs118203889

Variant names:

• chrM-12207-G-A
• rs118203889
• unassigned_transcript_4813:c.1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.12207G>A variant in MT-TS2 has been reported in three individuals with primary mitochondrial disease to date. One person had clinical features consistent with myoclonic epilepsy with ragged red fibers (MERRF) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS; PMID:16950817), had complex I deficiency in muscle, and had the variant present at 92% heteroplasmy in muscle. The variant was undetectable in the mother’s blood. Another individual was reported as part of a primary mitochondrial disease cohort (PMID:27450679) and was found to have the variant present at >60% in muscle and was undetectable in blood from the proband and mother. The variant was also seen in a Japanese family with diabetes, epilepsy, deafness, and developmental delay. The variant was found in the proband at 31.3% heteroplasmy in blood, 52.6% in saliva, and 73.9% in urinary sediment while the variant was found in the mother at 13.8%, 22.1%, and 29.4%, respectively (PMID:36967720; PS4_supporting). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is deleterious (76.4 percentile) and HmtVAR predicts it to be deleterious with a score of 0.5 (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance 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 May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120545/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNS2 unassigned_transcript_4813 missense
• Scores: Mitotip Pathogenic 16
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 O:1 Myopathy-/-Encephalopathy
• Conservation: PhyloP100: 0.419
• Publications: 1 publications found

Genes affected

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

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))

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

TRNH Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNS2	unassigned_transcript_4813	c.1G>A	p.Glu1Lys	missense_variant	Exon 1 of 1
ND5	unassigned_transcript_4815	c.-130G>A		upstream_gene_variant
TRNL2	unassigned_transcript_4814	c.-59G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.-130G>A		upstream_gene_variant		6		ENSP00000354813.2
MT-ND4	ENST00000361381.2	c.*70G>A		downstream_gene_variant		6		ENSP00000354961.2

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Myopathy-/-Encephalopathy

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:1 Other:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

MERRF/MELAS overlap syndrome Pathogenic:1

Sep 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

May 13, 2024

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.12207G>A variant in MT-TS2 has been reported in three individuals with primary mitochondrial disease to date. One person had clinical features consistent with myoclonic epilepsy with ragged red fibers (MERRF) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS; PMID: 16950817), had complex I deficiency in muscle, and had the variant present at 92% heteroplasmy in muscle. The variant was undetectable in the mother’s blood. Another individual was reported as part of a primary mitochondrial disease cohort (PMID: 27450679) and was found to have the variant present at >60% in muscle and was undetectable in blood from the proband and mother. The variant was also seen in a Japanese family with diabetes, epilepsy, deafness, and developmental delay. The variant was found in the proband at 31.3% heteroplasmy in blood, 52.6% in saliva, and 73.9% in urinary sediment while the variant was found in the mother at 13.8%, 22.1%, and 29.4%, respectively (PMID: 36967720; PS4_supporting). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is deleterious (76.4 percentile) and HmtVAR predicts it to be deleterious with a score of 0.5 (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance 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 May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP3, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	16
Hmtvar	Pathogenic	0.50
PhyloP100		0.42

Other links and lift over

dbSNP: rs118203889; hg19: chrM-12208;