M-9804-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000362079.2(MT-CO3):​c.598G>C​(p.Ala200Pro) variant causes a missense change. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A200T) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 2)
• Consequence: MT-CO3 ENST00000362079.2 missense
• Scores: Apogee2 Uncertain 0.46
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 No linked disesase in Mitomap
• 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 1 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP4: Apogee2 supports a benign effect, 0.4596199 < 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX3	unassigned_transcript_4806	c.598G>C	p.Ala200Pro	missense_variant	Exon 1 of 1
TRNG	unassigned_transcript_4807	c.-187G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO3	ENST00000362079.2	c.598G>C	p.Ala200Pro	missense_variant	Exon 1 of 1	6		ENSP00000354982.2
MT-TG	ENST00000387429.1	n.-187G>C		upstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.0 AC: 2

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Uncertain:1

Oct 17, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.9804G>C (YP_003024032.1:p.Ala200Pro) variant in MTCO3 gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PP4

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.46
Hmtvar	Pathogenic	0.84
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.31	T
DEOGEN2	Benign	0.17	T
LIST_S2	Benign	0.64	T
MutationAssessor	Pathogenic	5.0	H
PhyloP100		4.0
PROVEAN	Pathogenic	-4.5	D
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
GERP RS		4.3
Varity_R		0.85

Other links and lift over

dbSNP: rs200613617; hg19: chrM-9805;