M-8803-A-T
Variant summary
Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4
This summary comes from the ClinGen Evidence Repository: The m.8803A>T variant in MT-ATP6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 10, 2023. This variant has been reported twice in the medical literature in affected individuals but there was no attribution of pathogenic involvement in either case (one case had Leber Hereditary Optic Neuropathy, PMID 15465027; one case had Alzheimer disease, PMID 20700462). There are no other individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present at low frequency in population databases. The frequency in gnomAD v3.1.2 was 22/56,434 (0.039%) with all 22 being homoplasmic and in top level haplogroup H. The frequency in the MITOMAP GenBank sequences was 8/59,389 (0.013%); all eight of these individuals (100%) are in H5a haplogroup, with one of them being the individual with Alzheimer disease discussed above. The frequency of homoplasmic occurrences in the Helix dataset was 159/195,983 (0.081%); 152 of these Helix variants were in haplogroup H; seven were in haplogroup U. An additional five variants were reported as heteroplasmic; these were all in haplogroup H. Of note, the individual with Leber Hereditary Optic Neuropathy discussed above types to haplogroup U1a. Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign (>0.5%). The computational predictor APOGEE gives a consensus rating of benign with scores of 0.37 (“neutral”) in APOGEE1 and 0.101 (“likely benign” in APOGEE2; Min=0, Max=1), predicting no impact on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays found in the literature for this variant to date. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 10, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10581289/MONDO:0044970/015
Frequency
Consequence
ENST00000361899.2 missense
Scores
Clinical Significance
Conservation
Publications
- mitochondrial proton-transporting ATP synthase complex deficiencyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- periodic paralysis with later-onset distal motor neuropathyInheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
- mitochondrial diseaseInheritance: AR, Mitochondrial Classification: LIMITED Submitted by: Illumina, ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received -1 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP6 | unassigned_transcript_4805 | c.277A>T | p.Thr93Ser | missense_variant | Exon 1 of 1 | |||
| ATP8 | unassigned_transcript_4804 | c.*231A>T | downstream_gene_variant |
Ensembl
Frequencies
Mitomap
ClinVar
Submissions by phenotype
Mitochondrial disease Uncertain:1
The m.8803A>T variant in MT-ATP6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 10, 2023. This variant has been reported twice in the medical literature in affected individuals but there was no attribution of pathogenic involvement in either case (one case had Leber Hereditary Optic Neuropathy, PMID 15465027; one case had Alzheimer disease, PMID 20700462). There are no other individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present at low frequency in population databases. The frequency in gnomAD v3.1.2 was 22/56,434 (0.039%) with all 22 being homoplasmic and in top level haplogroup H. The frequency in the MITOMAP GenBank sequences was 8/59,389 (0.013%); all eight of these individuals (100%) are in H5a haplogroup, with one of them being the individual with Alzheimer disease discussed above. The frequency of homoplasmic occurrences in the Helix dataset was 159/195,983 (0.081%); 152 of these Helix variants were in haplogroup H; seven were in haplogroup U. An additional five variants were reported as heteroplasmic; these were all in haplogroup H. Of note, the individual with Leber Hereditary Optic Neuropathy discussed above types to haplogroup U1a. Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign (>0.5%). The computational predictor APOGEE gives a consensus rating of benign with scores of 0.37 (“neutral”) in APOGEE1 and 0.101 (“likely benign” in APOGEE2; Min=0, Max=1), predicting no impact on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays found in the literature for this variant to date. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 10, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. -
not provided Uncertain:1
- -
Leigh syndrome Benign:1
The NC_012920.1:m.8803A>T (YP_003024031.1:p.Thr93Ser) variant in MTATP6 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS4 -
Computational scores
Source: