rs200613617

chrM-9804-G-AchrM-9804-G-CchrM-9804-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PS1_Moderate BP4 BS2

The ENST00000362079.2(MT-CO3):c.598G>A(p.Ala200Thr) variant causes a missense change. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Mitomap GenBank: 𝑓 0.0030 (AC: 181)
• Consequence: MT-CO3 ENST00000362079.2 missense
• Scores: Apogee2 Uncertain 0.40
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:2 O:1 LHON-/-MS
• Conservation: PhyloP100: 4.01

Genes affected

COX3 (HGNC:):

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PS1: Transcript ENST00000362079.2 (MT-CO3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Apogee2 supports a benign effect, 0.3962503 < 0.5 .
• BS2: High AC in GnomadMitoHomoplasmic at 205

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COX3	COX3.1	c.598G>A	p.Ala200Thr	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-CO3	ENST00000362079.2	c.598G>A	p.Ala200Thr	missense_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

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: 0.00443 Hom.: 172

Mitomap

LHON-/-MS

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leber optic atrophy Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 29, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

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

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 21, 2017

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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 13, 2023

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. -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Oct 17, 2019

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
MutationTaster	Benign	8.5e-8	A
PROVEAN	Uncertain	-3.3	D
Sift	Benign	0.038	D
Sift4G	Uncertain	0.031	D
GERP RS		4.3
Varity_R		0.26

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200613617; hg19: chrM-9805;