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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNS1	unassigned_transcript_4800	c.10A>G	p.Met4Val	missense_variant	Exon 1 of 1
COX2	unassigned_transcript_4802	c.-81T>C		upstream_gene_variant
TRND	unassigned_transcript_4801	c.-13T>C		upstream_gene_variant
COX1	unassigned_transcript_4799	c.*60T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TS1	ENST00000387416.2	n.10A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-CO2	ENST00000361739.1	c.-81T>C		upstream_gene_variant		6		ENSP00000354876.1
MT-CO1	ENST00000361624.2	c.*60T>C		downstream_gene_variant		6		ENSP00000354499.2
MT-TD	ENST00000387419.1	n.-13T>C		upstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

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

Status: Reported

ClinVar

Significance: Uncertain significance

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

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1 Other:1

May 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

- -

Mitochondrial disease Uncertain:1

Aug 27, 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.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. -

Computational scores

Source: dbNSFP v4.3

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;