ENST00000361899.2:c.626T>C

Variant names:

• chrM-9152-T-C
• rs878853096
• ENST00000361899.2:c.626T>C

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The m.9152T>C (p.I209T) variant in MT-ATP6 has been reported in one case to date, in an individual with autism, fatigue, reflux, and constipation (PMID:30763462) who had the variant present at 23% in blood. The proband's healthy mother had the variant present at 10% in blood. There are no reported de novo occurrences to our knowledge. The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.47 (Min=0, Max=1), which predicts no damaging effect on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10581404/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.00030 (AC: 17)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Pathogenic 0.57
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 O:1 Patient-with-suspected-mitochondrial-disease
• Conservation: PhyloP100: 7.67
• Publications: 3 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 -1 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361899.2. 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-ATP6	ENST00000361899.2	TSL:6	c.626T>C	p.Ile209Thr	missense	Exon 1 of 1	ENSP00000354632.2	P00846
	MT-CO3	ENST00000362079.2	TSL:6	c.-55T>C		upstream_gene	N/A	ENSP00000354982.2	P00414

Frequencies

Mitomap GenBank AF: 0.00030 AC: 17

Gnomad homoplasmic AF: 0.00012 AC: 7 AN: 56430

Gnomad heteroplasmic AF: 0.000089 AC: 5 AN: 56430

Alfa AF: 0.000223 Hom.: 1

Mitomap

Disease(s): Patient-with-suspected-mitochondrial-disease

Status: Reported-[VUS]

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	1	-	Mitochondrial disease (1)
-	1	-	not provided (1)
-	-	-	Mitochondrial-DNA disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.57
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.0048	T
DEOGEN2	Benign	0.40	T
LIST_S2	Benign	0.77	T
MutationAssessor	Pathogenic	5.0	H
PhyloP100		7.7
PROVEAN	Pathogenic	-4.4	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.0
Varity_R		0.94

Other links and lift over

dbSNP: rs878853096; hg19: chrM-9153;