M-8529-G-A

Variant names:

• chrM-8529-G-A
• rs267606881
• ENST00000361851.1:c.164G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PS3_Supporting PM2_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
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 Apical-HCM
• Conservation: PhyloP100: 7.76
• Publications: 6 publications found

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

ACMG classification

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
ATP8	unassigned_transcript_4804	c.164G>A	p.Trp55*	stop_gained	Exon 1 of 1
ATP6	unassigned_transcript_4805	c.3G>A	p.Met1?	start_retained_variant	Exon 1 of 1
TRNK	unassigned_transcript_4803	c.*165G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP8	ENST00000361851.1	c.164G>A	p.Trp55*	stop_gained	Exon 1 of 1	6		ENSP00000355265.1
MT-ATP6	ENST00000361899.2	c.3G>A	p.Met1?	start_retained_variant	Exon 1 of 1	6		ENSP00000354632.2
MT-TK	ENST00000387421.1	n.*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

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

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

Other links and lift over

dbSNP: rs267606881; hg19: chrM-8530;