rs1556423632

Variant names:

• chrM-9191-T-C
• rs1556423632
• unassigned_transcript_4805:c.665T>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ATP6 missense
• Scores: Apogee2 Pathogenic 0.91
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 O:1 Leigh-Disease
• Conservation: PhyloP100: 7.69

Genes affected

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]

COX3 (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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-9191-T-C is Pathogenic according to our data. Variant chrM-9191-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40153.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.665T>C	p.Leu222Pro	missense_variant	Exon 1 of 1
COX3	unassigned_transcript_4806	c.-16T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

Leigh-Disease

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Mar 24, 2022

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.9191T>C (p.L222P) variant in MT-ATP6 has been reported once in the literature (PMID: 16217706, patient 2) in an individual with Leigh syndrome (94% heteroplasmy in muscle and 90% in fibroblasts; only testing done was MT-ATP6 and MT-ATP8 sequencing). This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals. This variant occurred de novo in this individual (absent in blood from mother and sister; PM6_supporting, PMID: 16217706). There are no large families reported in the literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.75 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Yeast model showed (1) failure to grow on glycerol (indicating at least an 80% reduction in ATP synthase activity/function), (2) 67-85% decrease in oxygen consumption, (3) <10% of control ATP synthesis, and (4) impaired ATPase assembly (PS3_supporting, PMID: 24316278). 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 consistent functional evidence of severe deleterious effect and rare nature of the variant, as well as being absent in healthy cohorts even at low heteroplasmy levels. In summary, this variant is classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on January 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PM2_supporting, PM6_supporting, PP3. -

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	0.91
Hmtvar	Pathogenic	0.87
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.13	D
DEOGEN2	Benign	0.28	T
LIST_S2	Uncertain	0.92	D
MutationAssessor	Pathogenic	5.1	H
PROVEAN	Pathogenic	-6.2	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.0
Varity_R		0.94

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556423632; hg19: chrM-9192;