chrM-8993-T-G

Position:

• chrM-8993-T-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2_Supporting PM6_Strong PS4 PP1_Moderate PS3_Supporting PM5 PP3

This summary comes from the ClinGen Evidence Repository: The m.8993T>G (p.L156R) variant in MT-ATP6 has been reported in >16 individuals with primary mitochondrial disease (PS4; PMIDs: 2137962, 8250532, 8240109, 7605802, 8505474, 9221962, 10208283, 16525806, 10660580). There are several reports of de novo occurrences of this variant (PM6_strong, PMIDs: 29602698, 27450679, 12134275). This variant is located at the same amino acid position as another well-known pathogenic variant, m.8993T>C (p.L156P) (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; PMIDs: 2137962, 1436530, 1550128, 8095070, 9221962). This variant is absent in population databases after removing known patients with mitochondrial disease (PM2_supporting). In silico tools (APOGEE) predict this variant to be pathogenic (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID:14998933, 8078883, 19875463). 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 March 22, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM2_supporting, PM5, PM6_strong, PP1_moderate, PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA250380/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:21 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 15 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.
• PM6: 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/exons	MANE	Protein	UniProt
ATP6	ATP6.1	c.467T>G	p.Leu156Arg	missense_variant	1/1		YP_003024031.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.467T>G	p.Leu156Arg	missense_variant	1/1			ENSP00000354632	P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome Pathogenic:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Sep 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Nov 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 16, 2024	Criteria applied: PS4,PM6_STR,PM5,PP1_MOD,PS3_SUP,PM2_SUP,PP3 -

Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 18, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2009	- -
Pathogenic, criteria provided, single submitter	research	Kids Research, The Children's Hospital at Westmead	-	- -

Mitochondrial disease Pathogenic:3

Pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Mar 22, 2021	The m.8993T>G (p.L156R) variant in MT-ATP6 has been reported in >16 individuals with primary mitochondrial disease (PS4; PMIDs: 2137962, 8250532, 8240109, 7605802, 8505474, 9221962, 10208283, 16525806, 10660580). There are several reports of de novo occurrences of this variant (PM6_strong, PMIDs: 29602698, 27450679, 12134275). This variant is located at the same amino acid position as another well-known pathogenic variant, m.8993T>C (p.L156P) (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; PMIDs: 2137962, 1436530, 1550128, 8095070, 9221962). This variant is absent in population databases after removing known patients with mitochondrial disease (PM2_supporting). In silico tools (APOGEE) predict this variant to be pathogenic (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 14998933, 8078883, 19875463). 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 March 22, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM2_supporting, PM5, PM6_strong, PP1_moderate, PP3). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 15, 2023	The MT-ATP6 c.467T>G (p.Leu156Arg) variant, also known as m.8993T>G variant, is a mitochondrial missense variant that results in the substitution of leucine at amino acid position 156 with arginine. Across a selection of the available literature, the c.467T>G variant has been identified in at least 16 unrelated individuals with primary mitochondrial disease (PMID: 2137962; PMID: 8250532; PMID: 9221962). Clinical features and onset of symptoms vary depending on the levels of heteroplasmy, with a direct correlation between levels of heteroplasmy and severity of symptoms. In general, affected individuals show 85-95% heteroplasmy in blood and other tissues. While the variant has been shown to segregate with the disorder in multiple families, there are several reports of the variant in a de novo state as well (PMID: 9221962; PMID: 27450679; PMID: 29602698). Another variant at the same amino acid position, c.467T>C (p.Leu156Pro), is also a well-known pathogenic variant for primary mitochondrial disease. The c.467T>G variant is not found in version 3.1.2 of the Genome Aggregation Database. Cybrid cell lines with this variant show ATP synthesis defects (PMID: 19875463). Based on the available evidence, the c.467T>G (p.Leu156Arg) variant is classified as pathogenic for primary mitochondrial disease. -
Pathogenic, no assertion criteria provided	clinical testing	Wellcome Centre for Mitochondrial Research, Newcastle University	May 22, 2017	- -

NARP syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2009	- -
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>G (YP_003024031.1:p.Leu156Arg) 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 -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 24, 2018	The m.8993T>G affects the MT-ATP6 gene, and this well-studied variant accounts of the majority of patients diagnosed with Mitochondrial DNA (mtDNA)-associated Leigh syndrome and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa; see GeneReviews: NBK1173). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Leber optic atrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Sep 22, 2022

- -

Rod-cone dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Ocular Genomics Institute, Massachusetts Eye and Ear

Apr 08, 2021

The MT-ATP6 c.467T>G variant was identified in an individual with retinitis pigmentosa with a presumed mitochondrial inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PS4, PP1. Based on this evidence we have classified this variant as Pathogenic. -

Cerebellar ataxia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 06, 2014

This variant has been previously reported as disease-causing and was found once in our laboratory homoplasmic in a 22-year-old female with ataxia, abnormal movements - inherited from a heteroplasmic mother -

Hypertelorism;C0151526:Premature birth;C0239234:Low-set ears;C0409348:Camptodactyly of finger;C0431659:Hypoplasia of scrotum;C0431904:Postaxial hand polydactyly;C1398522:Bilateral cleft lip and palate;C1827524:Wide intermamillary distance Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 09, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.97
Hmtvar	Pathogenic	0.91
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.14	D
DEOGEN2	Uncertain	0.42	T
LIST_S2	Benign	0.75	T
MutationAssessor	Pathogenic	5.3	H
MutationTaster	Benign	0.58	A
PROVEAN	Pathogenic	-5.2	D
Sift4G	Uncertain	0.0070	D
GERP RS		4.9
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: rs199476133; hg19: chrM-8994;