M-8839-G-C

Variant names:

• chrM-8839-G-C
• rs1556423547
• ENST00000361899.2:c.313G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000361899.2(MT-ATP6):​c.313G>C​(p.Ala105Pro) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A105V) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Pathogenic 0.93
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1 NARP-syndrome
• Conservation: PhyloP100: 6.53
• Publications: 0 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-ATP6 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• NARP syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• familial infantile bilateral striatal necrosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial proton-transporting ATP synthase complex deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited Leigh syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• maternally-inherited spastic paraplegia

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

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.93439424 >= 0.5 .

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.313G>C	p.Ala105Pro	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.313G>C	p.Ala105Pro	missense_variant	Exon 1 of 1	6		ENSP00000354632.2

Frequencies

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

Mitomap

Disease(s): NARP-syndrome

Status: Reported

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial disease Pathogenic:1

May 22, 2017

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Leigh syndrome Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.93
Hmtvar	Pathogenic	0.90
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.033	T
DEOGEN2	Benign	0.35	T
LIST_S2	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		6.5
PROVEAN	Pathogenic	-4.6	D
Sift4G	Pathogenic	0.0010	D
GERP RS		4.9
Varity_R		0.98

Other links and lift over

dbSNP: rs1556423547; hg19: chrM-8840;