ENST00000362079.2:c.598G>A

Variant names:

• chrM-9804-G-A
• rs200613617
• ENST00000362079.2:c.598G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS4_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The m.9804G>A (p.A200T) variant in MT-CO3 has been reported in seven unrelated individuals with primary mitochondrial disease (PS4_moderate; PMIDs: 8240356, 17895983, 11339587, 11579587, 30831606). Six cases had Leber Hereditary Optic Neuropathy (LHON; PMIDs: 8240356, 11339587, 11579587, 30831606) and the variant was reported to be homoplasmic in four, heteroplasmic in one (level not provided), and the level was not provided in another. Limited clinical details were available from the seventh case but this child was described as having encephalopathy and the variant present at homoplasmy (PMID:17895983). There were no reported de novo occurrences and there were no reports of the variant segregating with clinical manifestations in a family. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.296%, 183/61,883; gnomAD v3.1.2: 0.363%, 205/56,420 homoplasmic occurrences in addition to 15 heteroplasmic occurrences; Helix: 0.472%, 926/195,893 homoplasmic occurrences in addition to 30 heteroplasmic occurrences).The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.866 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 September 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340930/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0030 (AC: 181)
• Consequence: MT-CO3 ENST00000362079.2 missense
• Scores: Apogee2 Uncertain 0.40
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:4 B:2 O:1 LHON-/-MS
• Conservation: PhyloP100: 4.01
• Publications: 11 publications found

Genes affected

MT-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

TRNG (HGNC:7486): (mitochondrially encoded tRNA glycine)

TRNG Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PS4: 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
COX3	unassigned_transcript_4806	c.598G>A	p.Ala200Thr	missense_variant	Exon 1 of 1
TRNG	unassigned_transcript_4807	c.-187G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO3	ENST00000362079.2	c.598G>A	p.Ala200Thr	missense_variant	Exon 1 of 1	6		ENSP00000354982.2
MT-TG	ENST00000387429.1	n.-187G>A		upstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0030 AC: 181

Gnomad homoplasmic AF: 0.0036 AC: 205 AN: 56420

Gnomad heteroplasmic AF: 0.00027 AC: 15 AN: 56420

Alfa AF: 0.00436 Hom.: 172

Mitomap

Disease(s): LHON-/-MS

Status: Reported-[VUS]

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:4 Benign:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber optic atrophy Pathogenic:2 Other:1

Oct 29, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

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

- -

not specified Uncertain:1 Benign:1

Nov 13, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The m.9804G>A variant in MT-CO3 is classified as benign because it has been identified in 0.5% (128/25840) of homoplasmic European alleles by gnomAD (http://gnomad.broadinstitute.org). In addition it was found at 95% frequency in the H6c haplogroup. ACMG/AMP Criteria applied: BA1. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Uncertain:1

Sep 26, 2023

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.9804G>A (p.A200T) variant in MT-CO3 has been reported in seven unrelated individuals with primary mitochondrial disease (PS4_moderate; PMIDs: 8240356, 17895983, 11339587, 11579587, 30831606). Six cases had Leber Hereditary Optic Neuropathy (LHON; PMIDs: 8240356, 11339587, 11579587, 30831606) and the variant was reported to be homoplasmic in four, heteroplasmic in one (level not provided), and the level was not provided in another. Limited clinical details were available from the seventh case but this child was described as having encephalopathy and the variant present at homoplasmy (PMID: 17895983). There were no reported de novo occurrences and there were no reports of the variant segregating with clinical manifestations in a family. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.296%, 183/61,883; gnomAD v3.1.2: 0.363%, 205/56,420 homoplasmic occurrences in addition to 15 heteroplasmic occurrences; Helix: 0.472%, 926/195,893 homoplasmic occurrences in addition to 30 heteroplasmic occurrences).The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.866 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 September 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP3. -

See cases Uncertain:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PS1,PP3. This variant was detected in mitochondrial heteroplasmy state. -

not provided Uncertain:1

Nov 21, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The m.9804G>A variant (rs200613617) has been reported as a primary pathogenic variant involved in Leber's hereditary optic neuropathy (LOHN; Johns 1993, Dogulu 2001, Savontaus 1995), and as a secondary variant (Matsumoto 1999). Initial studies identified the variant in 4 independent families, while noting its absence from healthy controls (Johns 1993, Dogulu 2001). However, in one family, the m.9804G>A variant was present in 3 asymptomatic family members (Dogulu 2001). This variant has also been previously observed by our laboratory in two patients, one with optic atrophy and one with chronic myoclonic disorder, neither of whom carried other significant variant in the mitochondrial genome or in 108 nuclear-encoded genes with mitochondrial function. This variant is listed in Mitomap with an overall frequency of 0.28%, and is found in the H6c haplogroup with a frequency of 95%. No functional studies have been conducted to determine the impact of the m.9804G>A variant on complex IV function. While it is possible that m.9804G>A is the primary pathogenic variant in this patient, the frequency in the H6c haplogroup suggests that it is unlikely to be pathogenic; however, due to conflicting evidence in the literature, we cannot classify this variant with certainty. -

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.9804G>A (YP_003024032.1:p.Ala200Thr) variant in MTCO3 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.40
Hmtvar	Benign	0.25
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.34	T
DEOGEN2	Benign	0.084	T
LIST_S2	Benign	0.68	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.0
PROVEAN	Uncertain	-3.3	D
Sift	Benign	0.038	D
Sift4G	Uncertain	0.031	D
GERP RS		4.3
Varity_R		0.26
Mutation Taster		=36/64	disease causing

Other links and lift over

dbSNP: rs200613617; hg19: chrM-9805;