rs199476133

chrM-8993-T-CchrM-8993-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4 PS3_Supporting PP1_Moderate PM5 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:9 O:1 NARP-/-Leigh-Disease-/-MILS-/-other,NARP-/-Leigh-Disease-/-MILS-/-other
• Conservation: PhyloP100: 5.93

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6	ATP6.1	c.467T>C	p.Leu156Pro	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.467T>C	p.Leu156Pro	missense_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

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

Gnomad homoplasmic AF: 0.000018 AC: 1 AN: 56431

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56431

Mitomap

NARP-/-Leigh-Disease-/-MILS-/-other,NARP-/-Leigh-Disease-/-MILS-/-other

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Wellcome Centre for Mitochondrial Research, Newcastle University	May 22, 2017	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Feb 17, 2021	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). -

NARP syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Feb 22, 2024	- -
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.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:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Pediatric Department, Xiangya Hospital, Central South University	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2007

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Leber optic atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Ataxia and polyneuropathy, adult-onset Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2007

- -

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
MutationTaster	Benign	1.0	A
PROVEAN	Pathogenic	-6.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.9
Varity_R		0.99

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476133; hg19: chrM-8994;