ENST00000361899.2:c.277A>T

Variant names:

• chrM-8803-A-T
• rs878853020
• ENST00000361899.2:c.277A>T

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The m.8803A>T variant in MT-ATP6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 10, 2023. This variant has been reported twice in the medical literature in affected individuals but there was no attribution of pathogenic involvement in either case (one case had Leber Hereditary Optic Neuropathy, PMID 15465027; one case had Alzheimer disease, PMID 20700462). There are no other individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present at low frequency in population databases. The frequency in gnomAD v3.1.2 was 22/56,434 (0.039%) with all 22 being homoplasmic and in top level haplogroup H. The frequency in the MITOMAP GenBank sequences was 8/59,389 (0.013%); all eight of these individuals (100%) are in H5a haplogroup, with one of them being the individual with Alzheimer disease discussed above. The frequency of homoplasmic occurrences in the Helix dataset was 159/195,983 (0.081%); 152 of these Helix variants were in haplogroup H; seven were in haplogroup U. An additional five variants were reported as heteroplasmic; these were all in haplogroup H. Of note, the individual with Leber Hereditary Optic Neuropathy discussed above types to haplogroup U1a. Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign (>0.5%). The computational predictor APOGEE gives a consensus rating of benign with scores of 0.37 (“neutral”) in APOGEE1 and 0.101 (“likely benign” in APOGEE2; Min=0, Max=1), predicting no impact on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays found in the literature for this variant to date. 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 July 10, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10581289/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.00010 (AC: 8)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Benign 0.14
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 7.09
• Publications: 2 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]

MT-ATP8 Gene-Disease associations (from GenCC):

• mitochondrial proton-transporting ATP synthase complex deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• periodic paralysis with later-onset distal motor neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial disease

  Inheritance: AR, Mitochondrial Classification: LIMITED Submitted by: Illumina, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

• BP4: 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

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ATP6	ENST00000361899.2	TSL:6	c.277A>T	p.Thr93Ser	missense	Exon 1 of 1	ENSP00000354632.2	P00846
	MT-ATP8	ENST00000361851.1	TSL:6	c.*231A>T		downstream_gene	N/A	ENSP00000355265.1	P03928

Frequencies

Mitomap GenBank AF: 0.00010 AC: 8

Gnomad homoplasmic AF: 0.00039 AC: 22 AN: 56434

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56434

Alfa AF: 0.000224 Hom.: 1

Mitomap

No disease associated.

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	1	-	Mitochondrial disease (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.14
Hmtvar	Pathogenic	0.71
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.10	T
DEOGEN2	Benign	0.11	T
LIST_S2	Benign	0.62	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.1
PROVEAN	Uncertain	-3.5	D
Sift4G	Pathogenic	0.0010	D
GERP RS		3.5
Varity_R		0.77
Mutation Taster		=64/36	polymorphism

Other links and lift over

dbSNP: rs878853020; hg19: chrM-8804;