rs199476135

Variant names:

• chrM-9176-T-C
• rs199476135
• unassigned_transcript_4805:c.650T>C

Your query was ambiguous. Multiple possible variants found:

• chrM-9176-T-C
• chrM-9176-T-G

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 Pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ATP6 missense
• Scores: Apogee2 Pathogenic 0.97
• Clinical Significance: Pathogenic reviewed by expert panel P:15 U:1 O:1 FBSN-/-Leigh-Disease-/-Spinocerebellar-Ataxia,Leigh-Disease-/-Spastic-Paraplegia-/-Spinocerebellar-Ataxia
• Conservation: PhyloP100: 5.98

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-9176-T-C is Pathogenic according to our data. Variant chrM-9176-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9644.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.650T>C	p.Leu217Pro	missense_variant	Exon 1 of 1
COX3	unassigned_transcript_4806	c.-31T>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.

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56433

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56433

Mitomap

FBSN-/-Leigh-Disease-/-Spinocerebellar-Ataxia,Leigh-Disease-/-Spastic-Paraplegia-/-Spinocerebellar-Ataxia

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome Pathogenic:4 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Pediatric Department, Xiangya Hospital, Central South University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.9176T>C (YP_003024031.1:p.Leu217Pro) variant in MTATP6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM9, PM10, PP3, PP4 -

-

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 28, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PM5,PP1_MOD,PS3_SUP,PM2_SUP -

Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1 Pathogenic:2

Feb 28, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v3.1.2 dataset (heteroplasmic allele frequency: 0.005%, absent as homoplasmy). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (APOGEE:0.92>0.5). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (3billion dataset/ClinVar ID: VCV000009644). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 7668837, 9270604, 9501263, 9631394). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

NARP syndrome Pathogenic:2

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinGen has curated this variant. In addition, cosegregation with disease is observed in multiple families in multiple studies (PMID:21819970;9270604;7668837) -

Maternally-inherited spastic paraplegia Pathogenic:2

Jun 01, 2022

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

homoplasmic, Seq.depth: 1730x -

Nov 23, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PM5,PP1_MOD,PS3_SUP,PM2_SUP,PP3 -

Leber optic atrophy Pathogenic:2

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Striatonigral degeneration, infantile, mitochondrial Pathogenic:1

May 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Jun 30, 2022

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.9176T>C (p.L217P) variant in MT-ATP6 has been reported in more than 16 unrelated individuals with features of primary mitochondrial disease. Affected individuals had variable ages of onset (first months of life to 20s). Features included Leigh syndrome (including several cases with adult-onset Leigh syndrome) and NARP, as well as seizures, ataxia, muscle weakness, dystonia, axonal neuropathy, migraines, sensorineural hearing loss, hypertrophic cardiomyopathy, ophthalmoplegia, ptosis, and pigmentary retinopathy. Heteroplasmy levels were generally >90% in affected individuals (PS4; PMIDs: 17209980, 15709156, 11198506, 27408822, 30136164, 20656066, 21819970, 19747204, 9631394, 9501263, 9270604, 7668837). There are no reports of de novo occurrences of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 21819970, 9270604, 7668837). This variant is present in three sequences from GenBank dataset, however 2/3 sequences are from individuals with primary mitochondrial disease. This variant is not present in the homoplasmic state in any individuals in the gnomAD v3.1.2 dataset, however two individuals have this variant in the 50-60% heteroplasmy range and one in the 80-90% heteroplasmy range. There is one homoplasmic occurrence in the Helix dataset. This variant is located at the same amino acid position as another well-known pathogenic variant, m.9176T>G (p.L217R) (PM5). While cybrid studies were performed (PMID: 19160410), there was insufficient evidence reported to meet criteria for cybrid scoring per the specified guidelines for variant curation. Studies in yeast (PMID: 20056103) support the functional impact of this variant (PS3_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.92 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as 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 24, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PP1_moderate, PM5, PP3. -

Leigh syndrome, mitochondrial Pathogenic:1

May 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.97
Hmtvar	Pathogenic	0.92
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.083	D
DEOGEN2	Uncertain	0.42	T
LIST_S2	Benign	0.69	T
MutationAssessor	Pathogenic	5.0	H
PROVEAN	Pathogenic	-6.3	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.0
Varity_R		0.97

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476135; hg19: chrM-9177;