M-8528-T-C

Position:

• chrM-8528-T-C

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PVS1 PS1_Moderate 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

Genes affected

ATP6 (HGNC:):

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]

ACMG classification

Verdict is Pathogenic. Variant got 21 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000361899.2 (MT-ATP6) was described as [Pathogenic] in ClinVar as 9639
• 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/exons	MANE	Protein	UniProt
ATP6	ATP6.1	c.2T>C	p.Met1?	start_lost	1/1		YP_003024031.1
ATP8	ATP8.1	c.163T>C	p.Trp55Arg	missense_variant	1/1		YP_003024030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.2T>C	p.Met1?	start_lost	1/1			ENSP00000354632	P1
MT-ATP8	ENST00000361851.1	c.163T>C	p.Trp55Arg	missense_variant	1/1			ENSP00000355265	P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

Infantile-cardiomyopathy-/-hyperammonemia

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Jun 30, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 17, 2019

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2009

- -

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
MutationTaster	Benign	1.0	A;A
PROVEAN	Pathogenic	-5.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.1
Varity_R		0.69

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906422; hg19: chrM-8529;