M-9185-T-G

Variant names:

• chrM-9185-T-G
• rs199476138
• ENST00000361899.2:c.659T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM5 PP3

The ENST00000361899.2(MT-ATP6):​c.659T>G​(p.Leu220Arg) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 7/11 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L220P) has been classified as Pathogenic.

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 6)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Pathogenic 0.57
• Clinical Significance: Not reported in ClinVar No linked disesase in Mitomap
• Conservation: PhyloP100: 7.69
• Publications: 36 publications found

Genes affected

MT-ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

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]

MT-CO3 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 10 uncertain in ENST00000361899.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrM-9185-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 9647.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Apogee2 supports a deletorius effect, 0.56969935 >= 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.659T>G	p.Leu220Arg	missense_variant	Exon 1 of 1
COX3	unassigned_transcript_4806	c.-22T>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.659T>G	p.Leu220Arg	missense_variant	Exon 1 of 1	6		ENSP00000354632.2
MT-CO3	ENST00000362079.2	c.-22T>G		upstream_gene_variant		6		ENSP00000354982.2

Frequencies

Mitomap GenBank AF: 0.00010 AC: 6

Gnomad homoplasmic AF: 0.000035 AC: 2 AN: 56431

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56431

Mitomap

No disease associated.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.57
Hmtvar	Pathogenic	0.90
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.15	D
DEOGEN2	Benign	0.31	T
LIST_S2	Benign	0.71	T
MutationAssessor	Pathogenic	5.3	H
PhyloP100		7.7
PROVEAN	Pathogenic	-5.3	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.0
Varity_R		0.97

Other links and lift over

dbSNP: rs199476138; hg19: chrM-9186;