rs199476133

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_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:10O:1
NARP-/-Leigh-Disease-/-MILS-/-other,NARP-/-Leigh-Disease-/-MILS-/-other

Conservation

PhyloP100: 5.93
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
No frequency data in Mitomap. Probably very rare.
PP5
Variant M-8993-T-C is Pathogenic according to our data. Variant chrM-8993-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9642.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP6unassigned_transcript_4805 c.467T>C p.Leu156Pro missense_variant Exon 1 of 1
COX3unassigned_transcript_4806 c.-214T>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:
0.000018
AC:
1
AN:
56431
Gnomad heteroplasmic
AF:
0.000018
AC:
1
AN:
56431

Mitomap

NARP-/-Leigh-Disease-/-MILS-/-other,NARP-/-Leigh-Disease-/-MILS-/-other

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

NARP syndrome Pathogenic:3
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 -

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.8993T>C (YP_003024031.1:p.Leu156Pro) 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, PS3 -

Feb 22, 2024
Undiagnosed Diseases Network, NIH
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mitochondrial disease Pathogenic:2
Feb 17, 2021
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The m.8993T>C (p.L156P) variant in MT-ATP6 has been reported in >16 individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood; and who had features variably consistent with Leigh syndrome and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) (PS4; PMIDs: 8395787, 16532470, 30128709, 29101127, 28003964, 26265210, 22819295, 19046652, 18055910, 16049925, 10604142). Per our literature review and a recently published review, there are no published de novo occurrences of this variant (PMID: 30763462). This variant is located at the same amino acid position as another well-known pathogenic variant, m.8993T>G (p.L156R) (PM5). 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; PMID: 10604142). In silico tools predict this variant to be pathogenic (PP3). Cybrid studies (homoplasmic for this variant) showed reduced ATP production compared to Rho+ control cell lines (PS3_supporting; PMID: 19160410). 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 U24 Mitochondrial Disease Variant Curation Expert Panel on February 17, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM5, PP1_moderate, PP3). -

May 22, 2017
Wellcome Centre for Mitochondrial Research, Newcastle University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Leigh syndrome Pathogenic:1Other: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

- -

Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1 Pathogenic:1
Dec 01, 2007
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Pathogenic:1
Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Leber optic atrophy Pathogenic:1
May 04, 2022
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ataxia and polyneuropathy, adult-onset Pathogenic:1
Dec 01, 2007
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
0.97
Hmtvar
Pathogenic
0.90
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Uncertain
0.079
D
DEOGEN2
Uncertain
0.43
T
LIST_S2
Benign
0.69
T
MutationAssessor
Pathogenic
5.3
H
PROVEAN
Pathogenic
-6.0
D
Sift4G
Pathogenic
0.0
D
GERP RS
4.9
Varity_R
0.99

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199476133; hg19: chrM-8994; API