M-7445-A-T

Variant names:

• chrM-7445-A-T
• rs199474818
• ENST00000361624.2:c.1542A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The m.7445A>T (p.*514S) variant in MT-CO1 has been reported in one individual with primary mitochondrial disease to date (PMID:18639500). This person was Chinese and had severe hearing loss onset at age one year. There was no known precipitating event. The variant was homoplasmic in blood. There was no family history of hearing loss. This variant is present in population databases (Mitomap's 51,863 sequences: AF=0.049%; Helix's 196,554 sequences: AF=0.002%; gnomAD v3.1.2: absent). There are no in-silico prediction tools for a stop-loss variant in mitochondrial DNA, although this variant would not be expected to cause run-through due to the excision of the tRNA immediately adjacent. Another variant at this position has been classified as pathogenic – m.7445A>G (PM5_supporting). 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 July 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM5_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA414792846/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 3)
• Consequence: MT-CO1 ENST00000361624.2 stop_lost, splice_region
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1 DEAF,SNHL,SNHL
• Conservation: PhyloP100: -0.943
• Publications: 5 publications found

Genes affected

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]

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]

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

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

TRNS1 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 1 ACMG points.

• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361624.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CO1	ENST00000361624.2	TSL:6	c.1542A>T	p.Ter514Serext*?	stop_lost splice_region	Exon 1 of 1	ENSP00000354499.2
	MT-CO2	ENST00000361739.1	TSL:6	c.-141A>T		upstream_gene	N/A	ENSP00000354876.1
	MT-TD	ENST00000387419.1	TSL:6	n.-73A>T		upstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0 AC: 3

Mitomap

Disease(s): DEAF,SNHL,SNHL

Status: Reported,Cfrm-[P],Reported

ClinVar

Significance: Uncertain significance

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

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial non-syndromic sensorineural hearing loss 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

Mitochondrial disease Uncertain:1

Jul 08, 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.7445A>T (p.*514S) variant in MT-CO1 has been reported in one individual with primary mitochondrial disease to date (PMID: 18639500). This person was Chinese and had severe hearing loss onset at age one year. There was no known precipitating event. The variant was homoplasmic in blood. There was no family history of hearing loss. This variant is present in population databases (Mitomap's 51,863 sequences: AF=0.049%; Helix's 196,554 sequences: AF=0.002%; gnomAD v3.1.2: absent). There are no in-silico prediction tools for a stop-loss variant in mitochondrial DNA, although this variant would not be expected to cause run-through due to the excision of the tRNA immediately adjacent. Another variant at this position has been classified as pathogenic – m.7445A>G (PM5_supporting). 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 July 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM5_supporting.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.27	T
PhyloP100		-0.94
GERP RS		-0.79
Varity_R		0.24

Other links and lift over

dbSNP: rs199474818; hg19: chrM-7446;