rs794726857
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PS2_ModeratePM2_SupportingPS4_ModeratePP1_ModeratePS3_Supporting
This summary comes from the ClinGen Evidence Repository: The m.8969G>A (p.S148N) variant in MT-ATP6 has been reported in at least five individuals from four families in the literature with features including nephrotic syndrome, developmental delay, seizures, stroke-like episodes, muscle weakness, brain atrophy, agenesis of the corpus callosum, hearing loss, Wolff-Parkinson-White syndrome, increased fasting level of glucose, liver steatosis, and failure to thrive, with heteroplasmy levels ranging from 61-96% (PS4_moderate; PMIDs: 25037980, 29350304, 27812026, 27450679). Additionally, this expert panel knew of two local families with affected individuals with this variant that the expert panel agreed to include. The variant was de novo in two of the four families reported in the literature (PS2_moderate; PMIDs: 25037980, 27450679). This variant segregated with disease in multiple affected members in one family and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 29350304). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Studies in cybrids and yeast support the functional impact of this variant (PS3_supporting; PMID:27812026). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.57 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be 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 March 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PS2_moderate, PP1_moderate, PM2_supporting, PS3_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA199769/MONDO:0044970/014
Frequency
Consequence
ENST00000361899.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP6 | ATP6.1 use as main transcript | c.443G>A | p.Ser148Asn | 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.443G>A | p.Ser148Asn | missense_variant | 1/1 | ENSP00000354632 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Myopathy, lactic acidosis, and sideroblastic anemia 3 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2014 | - - |
Mitochondrial disease Pathogenic:1
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jun 30, 2022 | The m.8969G>A (p.S148N) variant in MT-ATP6 has been reported in at least five individuals from four families in the literature with features including nephrotic syndrome, developmental delay, seizures, stroke-like episodes, muscle weakness, brain atrophy, agenesis of the corpus callosum, hearing loss, Wolff-Parkinson-White syndrome, increased fasting level of glucose, liver steatosis, and failure to thrive, with heteroplasmy levels ranging from 61-96% (PS4_moderate; PMIDs: 25037980, 29350304, 27812026, 27450679). Additionally, this expert panel knew of two local families with affected individuals with this variant that the expert panel agreed to include. The variant was de novo in two of the four families reported in the literature (PS2_moderate; PMIDs: 25037980, 27450679). This variant segregated with disease in multiple affected members in one family and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 29350304). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Studies in cybrids and yeast support the functional impact of this variant (PS3_supporting; PMID: 27812026). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.57 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be 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 March 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS2_moderate, PP1_moderate, PM2_supporting, PS3_supporting, PP3. - |
MELAS syndrome Pathogenic:1
| 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.8969G>A (YP_003024031.1:p.Ser148Asn) 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 - |
Leber optic atrophy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at