M-8993-T-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4PP1_ModeratePS3_SupportingPM5PP3
This summary comes from the ClinGen Evidence Repository: 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 maternal 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA120596/MONDO:0044970/014
Frequency
Consequence
ENST00000361899.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP6 | ATP6.1 use as main transcript | c.467T>C | p.Leu156Pro | missense_variant | 1/1 | YP_003024031.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MT-ATP6 | ENST00000361899.2 | c.467T>C | p.Leu156Pro | missense_variant | 1/1 | ENSP00000354632 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
NARP syndrome Pathogenic:3
| Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
| Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 17, 2019 | 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 - |
| Pathogenic, no assertion criteria provided | clinical testing | Undiagnosed Diseases Network, NIH | Feb 22, 2024 | - - |
Mitochondrial disease Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Wellcome Centre for Mitochondrial Research, Newcastle University | May 22, 2017 | - - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Feb 17, 2021 | 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). - |
Leigh syndrome Pathogenic:1Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Pediatric Department, Xiangya Hospital, Central South University | - | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Leber optic atrophy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Ataxia and polyneuropathy, adult-onset Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at