M-8529-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PS3_SupportingPM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.8529G>A variant (resulting in p.Trp55X in MT-ATP8 and p.M1M in MT-ATP6) has been reported in one individual with primary mitochondrial disease (PMID:17953552). This is a male with hypertrophic cardiomyopathy, gross motor delay, exercise intolerance, dysarthria, ataxia, ophthalmoplegia, and elevated cerebrospinal fluid lactate. The variant was present at homoplasmy in muscle and fibroblasts. Although not included in this curation given additional details are not available, we are aware of one additional case by personal communication with ataxia and spastic paraplegia. There are no reported de novo occurrences of this variant to our knowledge. There are no reports of large families with this variant segregating with disease. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Cybrid studies showed that the homoplasmic mutant clones had statistically significant decreases in Complex V activity (PS3_supporting, PMID:17954552). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS3_supporting, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120593/MONDO:0044970/015

Frequency

Mitomap GenBank:
Absent

Consequence

MT-ATP8
ENST00000361851.1 stop_gained

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:1
Apical-HCM

Conservation

PhyloP100: 7.76

Publications

6 publications found
Variant links:
Genes affected
MT-ATP8 (HGNC:7415): (mitochondrially encoded ATP synthase 8) 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 multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]
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]
TRNK (HGNC:7489): (mitochondrially encoded tRNA lysine)
TRNK Gene-Disease associations (from GenCC):
  • Leigh syndrome
    Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
  • mitochondrial disease
    Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
  • maternally-inherited cardiomyopathy and hearing loss
    Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
  • MERRF syndrome
    Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP8unassigned_transcript_4804 c.164G>A p.Trp55* stop_gained Exon 1 of 1
ATP6unassigned_transcript_4805 c.3G>A p.Met1? start_retained_variant Exon 1 of 1
TRNKunassigned_transcript_4803 c.*165G>A downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MT-ATP8ENST00000361851.1 linkc.164G>A p.Trp55* stop_gained Exon 1 of 1 6 ENSP00000355265.1 P03928
MT-ATP6ENST00000361899.2 linkc.3G>A p.Met1? start_retained_variant Exon 1 of 1 6 ENSP00000354632.2 P00846
MT-TKENST00000387421.1 linkn.*165G>A downstream_gene_variant 6

Frequencies

Mitomap GenBank
The variant is not present, suggesting it is rare.
Alfa
AF:
0.00
Hom.:
0

Mitomap

Disease(s): Apical-HCM
Status: Reported
Publication(s): 17954552

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Cardiomyopathy, apical hypertrophic, and neuropathy Pathogenic:1
Mar 01, 2008
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Mitochondrial disease Uncertain:1
Aug 12, 2024
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
Significance:Uncertain significance
Review Status:reviewed by expert panel
Collection Method:curation

The m.8529G>A variant (resulting in p.Trp55X in MT-ATP8 and p.M1M in MT-ATP6) has been reported in one individual with primary mitochondrial disease (PMID: 17953552). This is a male with hypertrophic cardiomyopathy, gross motor delay, exercise intolerance, dysarthria, ataxia, ophthalmoplegia, and elevated cerebrospinal fluid lactate. The variant was present at homoplasmy in muscle and fibroblasts. Although not included in this curation given additional details are not available, we are aware of one additional case by personal communication with ataxia and spastic paraplegia. There are no reported de novo occurrences of this variant to our knowledge. There are no reports of large families with this variant segregating with disease. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Cybrid studies showed that the homoplasmic mutant clones had statistically significant decreases in Complex V activity (PS3_supporting, PMID: 17954552). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.59
D
DEOGEN2
Benign
0.22
T
LIST_S2
Uncertain
0.90
D
PhyloP100
7.8
PROVEAN
Uncertain
-3.3
D
GERP RS
5.1
Varity_R
0.76

Publications

Other links and lift over

dbSNP: rs267606881; hg19: chrM-8530; API