rs397507452

Variant names:

• chrM-7443-A-G
• rs397507452
• ENST00000361624.2:c.1540A>G

Your query was ambiguous. Multiple possible variants found:

• chrM-7443-A-G
• chrM-7443-A-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PS3_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.7443A>G (p.*514G) variant in MT-CO1 has been reported in one individual with primary mitochondrial disease to date (PMID:10577941), in a child enrolled at the School for Deaf and Blind in Mongolia. He was reported to have been deaf since infancy. The variant appeared to be homoplasmic. Information was not provided on the family history of this individual. There are no additional case reports to our knowledge. There are several occurrences of this variant in population databases (Mitomap: 1/61,134, gnomAD: 1/56,434, Helix: 4/195,893). Although there are several occurrences, the frequency is still low (PM2_supporting). 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. Functional studies showed inefficient processing (29% of wild type) by tRNAseZ in the presence of this variant (PS3_supporting; PMID:16361254). 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): PS3_supporting, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA347798/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: MT-CO1 ENST00000361624.2 stop_lost, splice_region
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1 DEAF
• Conservation: PhyloP100: -0.146
• Publications: 0 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 2 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.

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

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-CO1	ENST00000361624.2	TSL:6	c.1540A>G	p.Ter514Glyext*?	stop_lost splice_region	Exon 1 of 1	ENSP00000354499.2	P00395
	MT-CO2	ENST00000361739.1	TSL:6	c.-143A>G		upstream_gene	N/A	ENSP00000354876.1	P00403
	MT-TD	ENST00000387419.1	TSL:6	n.-75A>G		upstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0 AC: 1

Gnomad homoplasmic AF: 0.000018 AC: 1 AN: 56434

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56434

Mitomap

Disease(s): DEAF

Status: Reported

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial disease (1)
1	-	-	Mitochondrial non-syndromic sensorineural hearing loss (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
PhyloP100		-0.15
GERP RS		2.4
Varity_R		0.17

Other links and lift over

dbSNP: rs397507452; hg19: chrM-7444;