M-9176-T-G

Variant names:

• chrM-9176-T-G
• rs199476135
• ENST00000361899.2:c.650T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM5 PP1_Moderate PP3 PS3_Moderate PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.9176T>G (p.L217R) variant in MT-ATP6 has been reported in 9 individuals with features of primary mitochondrial disease from 3 families. Affected individuals had variable ages of onset (first months of life to 3 years old, one case with onset in late teens). Features included Leigh syndrome, seizures, ataxia, muscle weakness, dystonia, developmental regression with illness, axonal neuropathy, optic atrophy, and retinal dystrophy. Some individuals had gradual progression including one with onset in childhood but surviving to at least 40s. Others have progressed to death within months. Brain imaging in some individuals was consistent with Leigh syndrome and others with diffuse brain atrophy. Elevated blood and CSF lactate were noted. Heteroplasmy levels were >95% in multiple tissues for those with onset in childhood, 70% for gradually-progressive phenotype, and healthy family members had 28-50% heteroplasmy (PS4_supporting; PMIDs: 11245730, 11731285; Khailany et al., 2020 with no PMID). There are no reports of de novo occurrence of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 11245730, 11731285; Khailany et al., 2020 with no PMID). This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (one occurrence in GenBank sequences is from individual with mitochondrial disease; absent in gnomAD v3.1.2 and Helix databset; PM2_supporting). This variant is located at the same amino acid position as another well-known pathogenic variant, m.9176T>C (p.L217P) (PM5). Several studies in E. coli (PMID:11119722), yeast (PMID:19454486), and cybrids (PMID:19160410) support the functional impact of this variant and independent studies showed independent deleterious effects of the variant (PS3_moderate). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be 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 February 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_moderate, PS4_supporting, PP1_moderate, PM2_supporting, PM5, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340929/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Pathogenic 0.96
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 O:1 FBSN-/-Leigh-Disease-/-Spinocerebellar-Ataxia,Leigh-Disease-/-Spastic-Paraplegia-/-Spinocerebellar-Ataxia
• Conservation: PhyloP100: 5.98
• Publications: 31 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 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.650T>G	p.Leu217Arg	missense	Exon 1 of 1	ENSP00000354632.2	P00846
	MT-CO3	ENST00000362079.2	TSL:6	c.-31T>G		upstream_gene	N/A	ENSP00000354982.2	P00414

Frequencies

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

Mitomap

Disease(s): FBSN-/-Leigh-Disease-/-Spinocerebellar-Ataxia,Leigh-Disease-/-Spastic-Paraplegia-/-Spinocerebellar-Ataxia

Status: Cfrm-[P],Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Leber optic atrophy (1)
1	-	-	Leigh syndrome (2)
1	-	-	Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1 (1)
1	-	-	Mitochondrial disease (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.96
Hmtvar	Pathogenic	0.92
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.15	D
DEOGEN2	Benign	0.41	T
LIST_S2	Benign	0.74	T
MutationAssessor	Pathogenic	5.3	H
PhyloP100		6.0
PROVEAN	Pathogenic	-5.4	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.0
Varity_R		0.96

Other links and lift over

dbSNP: rs199476135; hg19: chrM-9177;