chrM-8993-T-C

Variant names:

• chrM-8993-T-C
• rs199476133
• ENST00000361899.2:c.467T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS4 PM5 PP1_Moderate PS3_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The m.8993T>C (p.L156P) variant in MT-ATP6 has been reported in >16 individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood; and who had features variably consistent with Leigh syndrome and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) (PS4; PMIDs: 8395787, 16532470, 30128709, 29101127, 28003964, 26265210, 22819295, 19046652, 18055910, 16049925, 10604142). Per our literature review and a recently published review, there are no published de novo occurrences of this variant (PMID:30763462). This variant is located at the same amino acid position as another well-known pathogenic variant, m.8993T>G (p.L156R) (PM5). 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; PMID:10604142). In silico tools predict this variant to be pathogenic (PP3). Cybrid studies (homoplasmic for this variant) showed reduced ATP production compared to Rho+ control cell lines (PS3_supporting; PMID:19160410). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a maternal manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on February 17, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM5, PP1_moderate, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA120596/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Pathogenic 0.97
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:1 NARP-/-Leigh-Disease-/-MILS-/-other,NARP-/-Leigh-Disease-/-MILS-/-other
• Conservation: PhyloP100: 5.93
• Publications: 65 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: Pathogenic. The variant received 10 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.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.467T>C	p.Leu156Pro	missense_variant	Exon 1 of 1
COX3	unassigned_transcript_4806	c.-214T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.467T>C	p.Leu156Pro	missense_variant	Exon 1 of 1	6		ENSP00000354632.2
MT-CO3	ENST00000362079.2	c.-214T>C		upstream_gene_variant		6		ENSP00000354982.2

Frequencies

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

Gnomad homoplasmic AF: 0.000018 AC: 1 AN: 56431

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56431

Mitomap

Disease(s): NARP-/-Leigh-Disease-/-MILS-/-other,NARP-/-Leigh-Disease-/-MILS-/-other

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

NARP syndrome Pathogenic:3

Feb 22, 2024

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.8993T>C (YP_003024031.1:p.Leu156Pro) 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, PS3 -

Leigh syndrome Pathogenic:2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 05, 2024

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This m.8993T>C missense variant has been reported in litterature (PMID: 33717984, 18055910). In silico prediction scores are in favour of a deleterious effect. Pathogenic variants in the MT-ATP6 gene are responsible for Leigh syndrome (OMIM #500017). According to the available evidence, this variant is considered to be pathogenic. -

-

Pediatric Department, Xiangya Hospital, Central South University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Pathogenic:2

May 22, 2017

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 17, 2021

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.8993T>C (p.L156P) variant in MT-ATP6 has been reported in >16 individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood; and who had features variably consistent with Leigh syndrome and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) (PS4; PMIDs: 8395787, 16532470, 30128709, 29101127, 28003964, 26265210, 22819295, 19046652, 18055910, 16049925, 10604142). Per our literature review and a recently published review, there are no published de novo occurrences of this variant (PMID: 30763462). This variant is located at the same amino acid position as another well-known pathogenic variant, m.8993T>G (p.L156R) (PM5). 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; PMID: 10604142). In silico tools predict this variant to be pathogenic (PP3). Cybrid studies (homoplasmic for this variant) showed reduced ATP production compared to Rho+ control cell lines (PS3_supporting; PMID: 19160410). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on February 17, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM5, PP1_moderate, PP3). -

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

Dec 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber optic atrophy Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia and polyneuropathy, adult-onset Pathogenic:1

Dec 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.97
Hmtvar	Pathogenic	0.90
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.079	D
DEOGEN2	Uncertain	0.43	T
LIST_S2	Benign	0.69	T
MutationAssessor	Pathogenic	5.3	H
PhyloP100		5.9
PROVEAN	Pathogenic	-6.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.9
Varity_R		0.99
Mutation Taster		=80/20	polymorphism

Other links and lift over

dbSNP: rs199476133; hg19: chrM-8994;