ENST00000361624.2:c.1541G>A

Variant names:

• chrM-7444-G-A
• rs199474822
• ENST00000361624.2:c.1541G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1 BP2

This summary comes from the ClinGen Evidence Repository: The m.7444G>A (p.term514K) in MT-CO1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. This variant has been reported in several individuals with features of primary mitochondrial disease beginning in 1992 (Leber Hereditary Optic Neuropathy or LHON, PMID:1322638; hearing loss, PMID:16500624), however other genetic etiologies were not excluded due to technical limitations at the time and this variant is now recognized to be present at high frequencies in population databases. Furthermore, this variant has been seen in individuals with other well-known pathogenic mitochondrial DNA variants (family with LHON and m.3460G>A, PMID:7901141; family with hearing loss and m.1555A>G, PMID:16152638; BP2). The variant was seen at homoplasmy in affected and unaffected family members in several of these publications precluding consideration of segregation evidence. There are no reported de novo occurrences of this variant to our knowledge. Some functional characterization was performed in patient cells, however abnormalities noted were nonspecific and other genetic etiologies were not assessed (PMID:1322638). This variant is present at considerable frequencies in population databases (BS1). The frequency in the MITOMAP GenBank sequences is 206/59,389 (0.347%; 12/12 individuals in Hg V7, 3/3 individuals in Hg H40b, 4/4 individuals in V7b, 4/4 individuals in W4b, 84/86 individuals in V7a, also seen in individuals from M22b, M38a, H11, HV20, P2, B2e, and others). The frequency in gnomAD v3.1.2 is 302/56,419 (0.535%). Indeed, there are 302 homoplasmic occurrences (seen in all populations except Amish and Middle Eastern, seen across every haplogroup listed; seen in individuals ages 30 years to >80 years) in addition to 10 heteroplasmic occurrences (seen in multiple populations, haplogroups, and heteroplasmy levels). The frequency in the Helix dataset is 775/195,983 (0.395%). Indeed, there are 775 homoplasmic occurrences (seen across many haplogroups) and 24 heteroplasmic occurrences (seen across many haplogroups). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely benign 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 June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BS1, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254851/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0035 (AC: 213)
• Consequence: MT-CO1 ENST00000361624.2 stop_lost, splice_region
• Clinical Significance: Likely benign reviewed by expert panel P:4 B:3 O:1 LHON-/-SNHL-/-DEAF-modulator
• Conservation: PhyloP100: 1.42
• Publications: 8 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: Likely_benign. The variant received -5 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX1	unassigned_transcript_4799	c.1541G>A	p.Ter514Lysext*?	stop_lost, splice_region_variant	Exon 1 of 1
COX2	unassigned_transcript_4802	c.-142G>A		upstream_gene_variant
TRND	unassigned_transcript_4801	c.-74G>A		upstream_gene_variant
TRNS1	unassigned_transcript_4800	c.*2C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO1	ENST00000361624.2	c.1541G>A	p.Ter514Lysext*?	stop_lost, splice_region_variant	Exon 1 of 1	6		ENSP00000354499.2
MT-CO2	ENST00000361739.1	c.-142G>A		upstream_gene_variant		6		ENSP00000354876.1
MT-TD	ENST00000387419.1	n.-74G>A		upstream_gene_variant		6
MT-TS1	ENST00000387416.2	n.*2C>T		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0035 AC: 213

Gnomad homoplasmic AF: 0.0054 AC: 302 AN: 56419

Gnomad heteroplasmic AF: 0.00018 AC: 10 AN: 56419

Alfa AF: 0.0147 Hom.: 65

Mitomap

Disease(s): LHON-/-SNHL-/-DEAF-modulator

Status: Reported-[LB]

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:4 Benign:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Oct 01, 2005

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

- -

not provided Pathogenic:1

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aminoglycoside-induced deafness Pathogenic:1

Sep 14, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leber optic atrophy Pathogenic:1

Oct 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome Benign:1

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.7444G>A (YP_003024028.1:p.Ter514LysextX4) variant in MTCO1 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2 -

Mitochondrial disease Benign:1

Jun 26, 2023

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The m.7444G>A (p.term514K) in MT-CO1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. This variant has been reported in several individuals with features of primary mitochondrial disease beginning in 1992 (Leber Hereditary Optic Neuropathy or LHON, PMID: 1322638; hearing loss, PMID: 16500624), however other genetic etiologies were not excluded due to technical limitations at the time and this variant is now recognized to be present at high frequencies in population databases. Furthermore, this variant has been seen in individuals with other well-known pathogenic mitochondrial DNA variants (family with LHON and m.3460G>A, PMID: 7901141; family with hearing loss and m.1555A>G, PMID: 16152638; BP2). The variant was seen at homoplasmy in affected and unaffected family members in several of these publications precluding consideration of segregation evidence. There are no reported de novo occurrences of this variant to our knowledge. Some functional characterization was performed in patient cells, however abnormalities noted were nonspecific and other genetic etiologies were not assessed (PMID: 1322638). This variant is present at considerable frequencies in population databases (BS1). The frequency in the MITOMAP GenBank sequences is 206/59,389 (0.347%; 12/12 individuals in Hg V7, 3/3 individuals in Hg H40b, 4/4 individuals in V7b, 4/4 individuals in W4b, 84/86 individuals in V7a, also seen in individuals from M22b, M38a, H11, HV20, P2, B2e, and others). The frequency in gnomAD v3.1.2 is 302/56,419 (0.535%). Indeed, there are 302 homoplasmic occurrences (seen in all populations except Amish and Middle Eastern, seen across every haplogroup listed; seen in individuals ages 30 years to >80 years) in addition to 10 heteroplasmic occurrences (seen in multiple populations, haplogroups, and heteroplasmy levels). The frequency in the Helix dataset is 775/195,983 (0.395%). Indeed, there are 775 homoplasmic occurrences (seen across many haplogroups) and 24 heteroplasmic occurrences (seen across many haplogroups). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely benign 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 June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BS1, BP2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
PhyloP100		1.4
GERP RS		-7.5
Varity_R		0.14

Other links and lift over

dbSNP: rs199474822; hg19: chrM-7445; COSMIC: COSV104668815; COSMIC: COSV104668815;