rs387906422

Variant names:

• chrM-8528-T-C
• rs387906422
• ENST00000361899.2:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The ENST00000361899.2(MT-ATP6):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ATP6 ENST00000361899.2 start_lost
• Scores: Apogee2 Pathogenic 0.76
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 Infantile-cardiomyopathy-/-hyperammonemia
• Conservation: PhyloP100: 7.70
• Publications: 10 publications found

Genes affected

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]

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]

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: Pathogenic. The variant received 19 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.759827 >= 0.5 .
• PP5: Variant M-8528-T-C is Pathogenic according to our data. Variant chrM-8528-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9640.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.2T>C	p.Met1?	start_lost	Exon 1 of 1
ATP8	unassigned_transcript_4804	c.163T>C	p.Trp55Arg	missense_variant	Exon 1 of 1
TRNK	unassigned_transcript_4803	c.*164T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 1	6		ENSP00000354632.2
MT-ATP8	ENST00000361851.1	c.163T>C	p.Trp55Arg	missense_variant	Exon 1 of 1	6		ENSP00000355265.1
MT-TK	ENST00000387421.1	n.*164T>C		downstream_gene_variant		6

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Mitomap

Disease(s): Infantile-cardiomyopathy-/-hyperammonemia

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Jun 30, 2022

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.8528T>C variant in MT-ATP6 (p.M1T), MT-ATP8 (p.W55R) has been reported in seven unrelated individuals with primary mitochondrial disease with lactic acidosis, hyperammonemia, and hypertrophic cardiomyopathy. The levels of the variant in affected individuals ranged from 15% to homoplasmic (PS4_moderate; PMIDs: 30642647, 33180048, 19188198). There are no reported de novo occurrences of this variant to our knowledge. The variant segregated with disease manifestations in three families. In the first report (PMID: 19188198), two healthy family members had lower levels of the variant than the proband (proband had variant at 92-98% in 5 tissues; unaffected mother had the variant at 15-25%; unaffected aunt at 0%). In the second report (PMID: 26803244), the proband had the variant present at 90% heteroplasmy in heart and 86% in fibroblasts at autopsy; the healthy mother had the variant present at 1.4% in fibroblasts. In the third report (PMID: 33180048), the proband was homoplasmic for the variant and the variant was heteroplasmic in his mother who had mild features (short stature, frequent migraines; 82% in blood, 89% in urine, and 59% in saliva; PP1). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.63 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given two gene products are affected by this variant and the consistent biochemical phenotype reported. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1, PM2_supporting, PP3. -

Histiocytoid cardiomyopathy Pathogenic:1

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.8528T>C (YP_003024031.1:p.Met1Thr) variant in MTATP6 gene (also (YP_003024030.1:p.Trp55Arg) variant in MTATP8 gene) is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS3, PM8, PM9, PP4, PP6. -

Cardiomyopathy, infantile hypertrophic Pathogenic:1

May 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.76
Hmtvar	Pathogenic	0.90
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	0.0091	T
DEOGEN2	Benign	0.31	T
LIST_S2	Uncertain	0.90	D
PhyloP100		7.7
PROVEAN	Pathogenic	-5.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.1
Varity_R		0.69
Mutation Taster		=52/148	disease causing

Other links and lift over

dbSNP: rs387906422; hg19: chrM-8529;