M-9176-T-G

Position:

• chrM-9176-T-G

Variant summary

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

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

Genes affected

ATP6 (HGNC:):

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6	ATP6.1	c.650T>G	p.Leu217Arg	missense_variant	1/1
COX3	COX3.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.650T>G	p.Leu217Arg	missense_variant	1/1			P1
MT-CO3	ENST00000362079.2			upstream_gene_variant				P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

FBSN-/-Leigh-Disease-/-Spinocerebellar-Ataxia,Leigh-Disease-/-Spastic-Paraplegia-/-Spinocerebellar-Ataxia

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 17, 2019	The NC_012920.1:m.9176T>G (YP_003024031.1:p.Leu217Arg) variant in MTATP6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM9, PM10, PP3, PP4, PP7 -

Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2009

- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Mar 24, 2022

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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Jun 17, 2021

- -

Leber optic atrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genomics England Pilot Project, Genomics England

-

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.90	A
PROVEAN	Pathogenic	-5.4	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.0
Varity_R		0.96

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199476135; hg19: chrM-9177;