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NC_012920.1(MT-ATP6):m.8993T>G AND Mitochondrial disease

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Mar 22, 2021
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000495419.3

Allele description

NC_012920.1(MT-ATP6):m.8993T>G

Genes:
  • MT-ATP8:mitochondrially encoded ATP synthase 8 [Gene - OMIM - HGNC]
  • MT-ND1:mitochondrially encoded NADH dehydrogenase 1 [Gene - OMIM - HGNC]
  • MT-ND2:mitochondrially encoded NADH dehydrogenase 2 [Gene - OMIM - HGNC]
  • MT-CO1:mitochondrially encoded cytochrome c oxidase I [Gene - OMIM - HGNC]
  • MT-CO2:mitochondrially encoded cytochrome c oxidase II [Gene - OMIM - HGNC]
  • MT-TD:mitochondrially encoded tRNA aspartic acid [Gene - OMIM - HGNC]
  • MT-TI:mitochondrially encoded tRNA isoleucine [Gene - OMIM - HGNC]
  • MT-TK:mitochondrially encoded tRNA lysine [Gene - OMIM - HGNC]
  • MT-TM:mitochondrially encoded tRNA methionine [Gene - OMIM - HGNC]
  • MT-TW:mitochondrially encoded tRNA tryptophan [Gene - OMIM - HGNC]
  • MT-ND3:mitochondrially encoded NADH dehydrogenase 3 [Gene - OMIM - HGNC]
  • MT-ND4:mitochondrially encoded NADH dehydrogenase 4 [Gene - OMIM - HGNC]
  • MT-ND4L:mitochondrially encoded NADH dehydrogenase 4L [Gene - OMIM - HGNC]
  • MT-ND5:mitochondrially encoded NADH dehydrogenase 5 [Gene - OMIM - HGNC]
  • MT-CO3:mitochondrially encoded cytochrome c oxidase III [Gene - OMIM - HGNC]
  • MT-TA:mitochondrially encoded tRNA alanine [Gene - OMIM - HGNC]
  • MT-TR:mitochondrially encoded tRNA arginine [Gene - OMIM - HGNC]
  • MT-TN:mitochondrially encoded tRNA asparagine [Gene - OMIM - HGNC]
  • MT-TC:mitochondrially encoded tRNA cysteine [Gene - OMIM - HGNC]
  • MT-TQ:mitochondrially encoded tRNA glutamine [Gene - OMIM - HGNC]
  • MT-TG:mitochondrially encoded tRNA glycine [Gene - OMIM - HGNC]
  • MT-TH:mitochondrially encoded tRNA histidine [Gene - OMIM - HGNC]
  • MT-TS1:mitochondrially encoded tRNA serine 1 (UCN) [Gene - OMIM - HGNC]
  • MT-TS2:mitochondrially encoded tRNA serine 2 (AGU/C) [Gene - OMIM - HGNC]
  • MT-TY:mitochondrially encoded tRNA tyrosine [Gene - OMIM - HGNC]
  • MT-ATP6:mitochondrially encoded ATP synthase 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Genomic location:
Preferred name:
NC_012920.1(MT-ATP6):m.8993T>G
Other names:
MTATP6, 8993T-G, LEU156ARG; L156R
HGVS:
  • NC_012920.1:m.8993T>G
  • NC_012920.1:g.8993T>G
  • m.8993T>G
  • p.Leu156Arg
Protein change:
LEU156ARG
Links:
Genetic Testing Registry (GTR): GTR000556568; Genetic Testing Registry (GTR): GTR000556575; OMIM: 516060.0001; dbSNP: rs199476133
NCBI 1000 Genomes Browser:
rs199476133
Observations:
1

Condition(s)

Name:
Mitochondrial disease
Synonyms:
Mitochondrial diseases; Mitochondrial disorder
Identifiers:
MONDO: MONDO:0044970; MeSH: D028361; MedGen: C0751651; Orphanet: 68380

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000577899Wellcome Centre for Mitochondrial Research, Newcastle University
no assertion criteria provided
Pathogenic
(May 22, 2017) 		germlineclinical testing

SCV001736753ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(McCormick et al. (Hum Mutat. 2020))		Pathogenic
(Mar 22, 2021) 		germlinecuration

PubMed (1)
[See all records that cite this PMID]

SCV004014679Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)		Pathogenic
(Mar 15, 2023) 		unknownclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation.

McCormick EM, Lott MT, Dulik MC, Shen L, Attimonelli M, Vitale O, Karaa A, Bai R, Pineda-Alvarez DE, Singh LN, Stanley CM, Wong S, Bhardwaj A, Merkurjev D, Mao R, Sondheimer N, Zhang S, Procaccio V, Wallace DC, Gai X, Falk MJ.

Hum Mutat. 2020 Dec;41(12):2028-2057. doi: 10.1002/humu.24107. Epub 2020 Nov 10.

PubMed [citation]
PMID:
32906214
PMCID:
PMC7717623

Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells.

D'Aurelio M, Vives-Bauza C, Davidson MM, Manfredi G.

Hum Mol Genet. 2010 Jan 15;19(2):374-86. doi: 10.1093/hmg/ddp503. Epub 2009 Oct 29.

PubMed [citation]
PMID:
19875463
PMCID:
PMC2796897
See all PubMed Citations (7)

Details of each submission

From Wellcome Centre for Mitochondrial Research, Newcastle University, SCV000577899.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen, SCV001736753.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services, Illumina, SCV004014679.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 16, 2025