rs587776440
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2_SupportingPP3PM6_SupportingPS4_ModeratePM5PS3_Supporting
This summary comes from the ClinGen Evidence Repository: The m.13514A>G (p.D393G) variant in MT-ND5 has been reported in at least 12 unrelated individuals with primary mitochondrial disease with onset ranging from childhood to adulthood and features variably consistent with Leigh syndrome and MELAS, as well as hypertrophic cardiomyopathy, optic atrophy, and neuropathy (PS4_moderate; PMIDs: 26341968, 25974876, 32504279, 20972245, 23847141, 21712854, 15576045, 14684687, 11198278). Heteroplasmy levels in affected individuals ranged from 55-70% in muscle, 12-55% in fibroblasts, 4-50% in blood, and 90% heart. This variant has been identified as a de novo occurrence in at least two probands with primary mitochondrial disease (PM6_supporting; PMIDs: 14684687, 11198278). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Another variant at this amino acid position leading to a different amino acid change is classified as pathogenic by this Expert Panel – m.13513G>A (p. D393N, PM5). Cybrid studies showed a tight correlation between higher heteroplasmy level and lower complex I activity (PS3_supporting, PMID:11198278). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (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 May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PM6_supporting, PM2_supporting, PM5, PS3_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA345918/MONDO:0044970/014
Frequency
Consequence
ENST00000361567.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-ND5 | ENST00000361567.2 | c.1178A>G | p.Asp393Gly | missense_variant | 1/1 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Leigh syndrome Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
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.13514A>G (YP_003024036.1:p.Asp393Gly) variant in MTND5 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS3 - |
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.13514A>G (p.D393G) variant in MT-ND5 has been reported in at least 12 unrelated individuals with primary mitochondrial disease with onset ranging from childhood to adulthood and features variably consistent with Leigh syndrome and MELAS, as well as hypertrophic cardiomyopathy, optic atrophy, and neuropathy (PS4_moderate; PMIDs: 26341968, 25974876, 32504279, 20972245, 23847141, 21712854, 15576045, 14684687, 11198278). Heteroplasmy levels in affected individuals ranged from 55-70% in muscle, 12-55% in fibroblasts, 4-50% in blood, and 90% heart. This variant has been identified as a de novo occurrence in at least two probands with primary mitochondrial disease (PM6_supporting; PMIDs: 14684687, 11198278). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Another variant at this amino acid position leading to a different amino acid change is classified as pathogenic by this Expert Panel – m.13513G>A (p. D393N, PM5). Cybrid studies showed a tight correlation between higher heteroplasmy level and lower complex I activity (PS3_supporting, PMID: 11198278). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.95 (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 May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_supporting, PM2_supporting, PM5, PS3_supporting, PP3. - |
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at