chrM-7505-T-C

Variant names:

• chrM-7505-T-C
• rs724159989
• unassigned_transcript_4800:c.10A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3 PS3_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.7505T>C variant in MT-TS1 has been reported in two families with primary mitochondrial disease. Affected individuals had nonsyndromic hearing loss (PMIDs: 20153673, 33638616). The variant was present at homoplasmy in affected and unaffected family members. There are no reported de novo occurrences of this variant. There is one homoplasmic occurrence of this variant in the Helix dataset and this variant is absent in the MITOMAP GenBank dataset and in gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (58.6 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). Cybrid studies support the functional impact of this variant as they showed the variant was associated with decreased levels of tRNASer(UCN), altered conformation of the tRNA, altered stability of tRNASer(UCN), variable reductions of mitochondrial proteins, decreased enzymatic activities of mitochondrial respiratory chain complexes, decreased respiration, and increased reactive oxygen species (PS3_moderate; PMID:20153673). 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 August 27, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PP3, PS3_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261262/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNS1 unassigned_transcript_4800 missense
• Scores: Mitotip Uncertain 13
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 O:1 Maternally-inherited-hearing-loss
• Conservation: PhyloP100: 2.70
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PS3: 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.

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.10A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-CO2	ENST00000361739.1	TSL:6	c.-81T>C		upstream_gene	N/A	ENSP00000354876.1	P00403
	MT-CO1	ENST00000361624.2	TSL:6	c.*60T>C		downstream_gene	N/A	ENSP00000354499.2	P00395

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

Disease(s): Maternally-inherited-hearing-loss

Status: Reported

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)
-	1	-	Mitochondrial disease (1)
1	-	-	Mitochondrial non-syndromic sensorineural hearing loss (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	13
Hmtvar	Pathogenic	0.65
PhyloP100		2.7

Other links and lift over

dbSNP: rs724159989; hg19: chrM-7506;