rs387906422

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PS4_Moderate PP3 PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120595/MONDO:0044970/015

• 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: Likely_pathogenic. The variant received 5 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361899.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ATP6	ENST00000361899.2	TSL:6	c.2T>C	p.Met1?	start_lost	Exon 1 of 1	ENSP00000354632.2
	MT-ATP8	ENST00000361851.1	TSL:6	c.163T>C	p.Trp55Arg	missense	Exon 1 of 1	ENSP00000355265.1
	MT-TK	ENST00000387421.1	TSL:6	n.*164T>C		downstream_gene	N/A

Frequencies

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

Mitomap

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

Status: Cfrm-[LP]

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiomyopathy, infantile hypertrophic (1)
1	-	-	Histiocytoid cardiomyopathy (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

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;