chrM-9804-G-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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000362079.2. 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-CO3	ENST00000362079.2	TSL:6	c.598G>A	p.Ala200Thr	missense	Exon 1 of 1	ENSP00000354982.2	P00414
	MT-TG	ENST00000387429.1	TSL:6	n.-187G>A		upstream_gene	N/A

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

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Leber optic atrophy (3)
-	1	1	not specified (2)
-	-	1	Leigh syndrome (1)
-	1	-	Mitochondrial disease (1)
-	1	-	not provided (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

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;