rs1556423632

Variant names:

• chrM-9191-T-C
• rs1556423632
• ENST00000361899.2:c.665T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 4 ACMG points: 4P and 0B. PM6_Supporting PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.9191T>C (p.L222P) variant in MT-ATP6 has been reported once in the literature (PMID:16217706, patient 2) in an individual with Leigh syndrome (94% heteroplasmy in muscle and 90% in fibroblasts; only testing done was MT-ATP6 and MT-ATP8 sequencing). This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals. This variant occurred de novo in this individual (absent in blood from mother and sister; PM6_supporting, PMID:16217706). There are no large families reported in the literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.75 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Yeast model showed (1) failure to grow on glycerol (indicating at least an 80% reduction in ATP synthase activity/function), (2) 67-85% decrease in oxygen consumption, (3) <10% of control ATP synthesis, and (4) impaired ATPase assembly (PS3_supporting, PMID:24316278). This variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given consistent functional evidence of severe deleterious effect and rare nature of the variant, as well as being absent in healthy cohorts even at low heteroplasmy levels. In summary, this variant is classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on January 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PM2_supporting, PM6_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA345914/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Pathogenic 0.91
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 O:1 Leigh-Disease
• Conservation: PhyloP100: 7.69
• Publications: 0 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: Likely_pathogenic. The variant received 4 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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: 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.665T>C	p.Leu222Pro	missense	Exon 1 of 1	ENSP00000354632.2	P00846
	MT-CO3	ENST00000362079.2	TSL:6	c.-16T>C		upstream_gene	N/A	ENSP00000354982.2	P00414

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Leigh-Disease

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial disease (1)
-	-	-	Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.91
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.13	D
DEOGEN2	Benign	0.28	T
LIST_S2	Uncertain	0.92	D
MutationAssessor	Pathogenic	5.1	H
PhyloP100		7.7
PROVEAN	Pathogenic	-6.2	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.0
Varity_R		0.94
Mutation Taster		=67/33	polymorphism

Other links and lift over

dbSNP: rs1556423632; hg19: chrM-9192;