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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387416.2. 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-TS1	ENST00000387416.2	TSL:6	n.3A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-CO2	ENST00000361739.1	TSL:6	c.-74T>C		upstream_gene	N/A	ENSP00000354876.1	P00403
	MT-CO1	ENST00000361624.2	TSL:6	c.*67T>C		downstream_gene	N/A	ENSP00000354499.2	P00395

Frequencies

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

Mitomap

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

Status: Reported

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	MERRF/MELAS overlap syndrome (2)
1	-	-	Limb ataxia (1)
1	-	-	MELAS syndrome (2)
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)
1	-	-	Mitochondrial cytochrome c oxidase deficiency (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

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;