rs878852994

Variant names:

• chrM-8704-A-G
• rs878852994
• ENST00000361899.2:c.178A>G

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.8704A>G (p.M60V) variant in MT-ATP6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on September 26, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present in population databases and is seen in individuals from several different haplogroups (MITOMAP: 0.039%, 24/61,883; gnomAD v3.1.2: 0.023%, 13/56,434 homoplasmic occurrences; Helix: 0.009%, 18/195,893 homoplasmic occurrences in addition to three heteroplasmic occurrences). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.37 (Min=0, Max=1), which predicts no effect on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported for this variant. 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 September 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10581258/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.00040 (AC: 24)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Benign 0.0078
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 6.33
• Publications: 5 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.178A>G	p.Met60Val	missense	Exon 1 of 1	ENSP00000354632.2	P00846
	MT-ATP8	ENST00000361851.1	TSL:6	c.*132A>G		downstream_gene	N/A	ENSP00000355265.1	P03928

Frequencies

Mitomap GenBank AF: 0.00040 AC: 24

Gnomad homoplasmic AF: 0.00023 AC: 13 AN: 56434

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56434

Mitomap

No disease associated.

ClinVar

ClinVar submissions

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	0.0078
Hmtvar	Benign	0.15
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.58	T
PhyloP100		6.3
GERP RS		3.5
Varity_R		0.21
Mutation Taster		=78/122	disease causing

Other links and lift over

dbSNP: rs878852994; hg19: chrM-8705;