rs1057516063

Variant names:

• chrM-9166-T-C
• rs1057516063
• ENST00000361899.2:c.640T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1 PM2 BP4 BS2

The ENST00000361899.2(MT-ATP6):​c.640T>C​(p.Phe214Leu) variant causes a missense change. 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. F214S) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Uncertain 0.42
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1 EXIT+more-/-bilateral-optic-neuropathy
• Conservation: PhyloP100: 5.95
• Publications: 1 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-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO3 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cytochrome-c oxidase deficiency disease

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

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 7 uncertain in ENST00000361899.2
• PM2: Very low frequency in mitomap database: 0.0
• BP4: Apogee2 supports a benign effect, 0.42470115 < 0.5 .
• BS2: High AC in GnomadMitoHomoplasmic at 4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.640T>C	p.Phe214Leu	missense_variant	Exon 1 of 1
COX3	unassigned_transcript_4806	c.-41T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.640T>C	p.Phe214Leu	missense_variant	Exon 1 of 1	6		ENSP00000354632.2
MT-CO3	ENST00000362079.2	c.-41T>C		upstream_gene_variant		6		ENSP00000354982.2

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Gnomad homoplasmic AF: 0.000071 AC: 4 AN: 56429

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56429

Alfa AF: 0.000223 Hom.: 1

Mitomap

Disease(s): EXIT+more-/-bilateral-optic-neuropathy

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Oct 01, 2019

Service de Génétique Médicale, Centre Hospitalier Universitaire de Nice-Université Côte d'Azur

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: in vitro

Our patient had the variant m.9166T>C, p.Phe214Leu withProximal muscle weakness, exercise intolerance, myalgia, episodic rhabdomyolysis, and hyperlactatemia -

Optic neuropathy Pathogenic:1

Nov 21, 2016

Center for Neuroscience and Cell Biology, University of Coimbra, Portugal

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Leigh syndrome Uncertain:1

Oct 17, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.9166T>C (YP_003024031.1:p.Phe214Leu) variant in MTATP6 gene is interpretated to be a Uncertain Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PP3, PP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Uncertain	0.42
Hmtvar	Pathogenic	0.85
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.10	D
DEOGEN2	Benign	0.38	T
LIST_S2	Uncertain	0.88	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		5.9
PROVEAN	Pathogenic	-5.2	D
Sift4G	Uncertain	0.0080	D
GERP RS		5.0
Varity_R		0.88
Mutation Taster		=34/66	disease causing

Other links and lift over

dbSNP: rs1057516063; hg19: chrM-9167;