rs199474817

Variant names:

• chrM-7512-T-C
• rs199474817
• unassigned_transcript_4800:c.3A>G

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.7512T>C variant in MT-TS1 has been reported in four unrelated individuals with primary mitochondrial disease (PS4_moderate; PMIDs: 7669057, 17894844, 9778262). Clinical features in affected individuals include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) as well as seizures, cognitive decline, dementia, muscle atrophy, muscle weakness, ataxia, developmental regression, and sensorineural hearing loss. Muscle biopsy in some cases showed ragged red fibers. Heteroplasmy levels in affected individuals ranged from 24% to homoplasmy. There are no reported de novo occurrences of this variant reported to our knowledge. The variant segregated with clinical features in all reported families (PP1_moderate; PMIDs: 7669057, 17894844, 9778262). This variant is absent in the GenBank dataset and gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (64.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). Single fiber analysis showed significantly higher levels of the variant in COX-negative fibers (n=10, median 97%, range: 94–99%) compared with COX-positive fibers (n=10, median 36%, range: 12–91%) (PS3_supporting, PMID:17894844). 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 July 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120546/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNS1 unassigned_transcript_4800 synonymous
• Scores: Mitotip Uncertain 14
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 O:1 PEM-/-MERME-/-MELAS
• Conservation: PhyloP100: 2.12
• Publications: 3 publications found

Genes affected

TRNS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))

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-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

TRND (HGNC:7478): (mitochondrially encoded tRNA aspartic acid)

TRND Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNS1	unassigned_transcript_4800	c.3A>G	p.Glu1Glu	synonymous_variant	Exon 1 of 1
COX2	unassigned_transcript_4802	c.-74T>C		upstream_gene_variant
TRND	unassigned_transcript_4801	c.-6T>C		upstream_gene_variant
COX1	unassigned_transcript_4799	c.*67T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TS1	ENST00000387416.2	n.3A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-CO2	ENST00000361739.1	c.-74T>C		upstream_gene_variant		6		ENSP00000354876.1
MT-CO1	ENST00000361624.2	c.*67T>C		downstream_gene_variant		6		ENSP00000354499.2
MT-TD	ENST00000387419.1	n.-6T>C		upstream_gene_variant		6

Frequencies

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

Mitomap

Disease(s): PEM-/-MERME-/-MELAS

Status: Reported

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

MERRF/MELAS overlap syndrome Pathogenic:2

Jun 30, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VAF 50% heteroplasmy in blood, several affected family members -

Nov 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

MELAS syndrome Pathogenic:1 Other:1

Jul 12, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.7512T>C variant in MT-TS1 gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PS5, PP3 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Jul 08, 2024

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.7512T>C variant in MT-TS1 has been reported in four unrelated individuals with primary mitochondrial disease (PS4_moderate; PMIDs: 7669057, 17894844, 9778262). Clinical features in affected individuals include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) as well as seizures, cognitive decline, dementia, muscle atrophy, muscle weakness, ataxia, developmental regression, and sensorineural hearing loss. Muscle biopsy in some cases showed ragged red fibers. Heteroplasmy levels in affected individuals ranged from 24% to homoplasmy. There are no reported de novo occurrences of this variant reported to our knowledge. The variant segregated with clinical features in all reported families (PP1_moderate; PMIDs: 7669057, 17894844, 9778262). This variant is absent in the GenBank dataset and gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (64.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.75 (PP3). Single fiber analysis showed significantly higher levels of the variant in COX-negative fibers (n=10, median 97%, range: 94–99%) compared with COX-positive fibers (n=10, median 36%, range: 12–91%) (PS3_supporting, PMID: 17894844). 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 July 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3, PS3_supporting. -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Limb ataxia Pathogenic:1

Jul 23, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reviewed by ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as Likely pathogenic. -

Mitochondrial cytochrome c oxidase deficiency Pathogenic:1

Nov 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	14
Hmtvar	Pathogenic	0.75
PhyloP100		2.1

Other links and lift over

dbSNP: rs199474817; hg19: chrM-7513;