Variant: m.13513G>A

CA120632

9702 (ClinVar)

Gene: MT-ND5

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 7dcf79c3-61e2-40bb-bb3a-06d45c7c2c23

HGVS expressions

NC_012920.1:m.13513G>A
J01415.2:m.13513G>A
ENST00000361567.2:n.1177G>A

Pathogenic

• Met criteria codes: PS4 PP3 PM5 PM6_Strong PP1_Moderate

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.13513G>A (p. D393N) variant in MT-ND5 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with onset typically in childhood with some reports of onset in adolescence who had features variably consistent with Leigh syndrome, MELAS and MELAS-like, and/or mitochondrial encephalopathy (PS4; PMID: 25681084; PMID: 27344355; PMID: 30128709; PMID: 12624137; PMID: 14520659; PMID: 17400793; PMID: 18495510). This variant has been identified as a de novo occurrence in at least 5 probands with primary mitochondrial disease (PM6_strong; PMID: 27344355; PMID: 17400793; PMID: 18495510). This variant heteroplasmy level segregated with severity in 6 families where healthy mothers were found to have the variant at low heteroplasmy levels (PP1_moderate; PMID: 25681084; PMID: 12624137; PMID: 14520659). Another variant at this amino acid position leading to a different amino acid change is classified as pathogenic by mitomap.org and ClinVar – m.13514A>G (p.D393G; PM5). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.97 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6_strong, PM5, PP1_moderate, PP3).

Met criteria codes

• PS4: This variant has been reported in >16 individuals with primary mitochondrial disease with onset typically in childhood with some reports of onset in adolescence who had features variably consistent with Leigh syndrome, MELAS and MELAS-like, and/or mitochondrial encephalopathy (PS4; PMID: 25681084; PMID: 27344355; PMID: 30128709; PMID: 12624137; PMID: 14520659; PMID: 17400793; PMID: 18495510).
• PP3: APOGEE: 0.97 - pathogenic
• PM5: m.13514A>G (p.D393G) confirmed pathogenic in MITOMAP and ClinVar (one submission)
• PM6_Strong: This variant has been identified as a de novo occurrence in at least 5 probands with primary mitochondrial disease. Per SVI de novo guidance (Phenotype consistent with gene but not highly specific), total is 2.5 points (0.5 from Patient 1 in PMID: 18495510 + 0.5 from Patient 2 in PMID: 18495510 + 0.5 from Patient 3 in PMID: 17400793 + 0.5 from Patient 4 in PMID: 17400793 + 0.5 from case in PMID: 27344355)
• PP1_Moderate: This variant heteroplasmy level segregated with severity in 6 families where healthy mothers were found to have the variant at low heteroplasmy levels (PP1_moderate; PMID: 25681084; PMID: 12624137; PMID: 14520659).

Approved on: 2021-10-26

Published on: 2021-10-26