Variant: NC_012920.1:m.13379A>G

CA414817725

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 906267e0-9d37-42dd-b5c2-bb5c32365865

HGVS expressions

NC_012920.1:m.13379A>G
J01415.2:m.13379A>G
ENST00000361567.2:n.1043A>G

Uncertain Significance

• Met criteria codes: PM2_Supporting PS4_Supporting PP3

• Not Met criteria codes: PVS1 PS2 PS3 PS1 PP1 PM5 PM6

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.13379A>G (p.H348R) variant in MT-ND5 has been reported in three individuals with LHON from two families (PMIDs: 31669237, 34177762; PS4_supporting). The two related individuals with LHON had this variant present at homoplasmy in blood and were haplogroup J (PMID: 34177762). No other details were provided on the family history of these two individuals. The third individual with LHON had the variant present at 47% in blood, 72% in urine, and homoplasmic in fibroblasts, and was haplogroup H5b. His healthy mother had the variant present at 45% blood, 78% urine, and not performed in fibroblasts, This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.56 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no functional studies reported on this variant. 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 Mitochondrial Disease Variant Curation Expert Panel on May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3.

Met criteria codes

• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
• PS4_Supporting: The m.13379A>G (p.H348R) variant in MT-ND5 has been reported in three individuals with LHON from two families (PMIDs: 31669237, 34177762; PS4_supporting). The two related individuals with LHON had this variant present at homoplasmy in blood and were haplogroup J (PMID: 34177762). No other details were provided on the family history of these two individuals. The third individual with LHON had the variant present at 47% in blood, 72% in urine, and homoplasmic in fibroblasts, and was haplogroup H5b. His healthy mother had the variant present at 45% blood, 78% urine, and not performed in fibroblasts,
• PP3: The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.56 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).

Not Met criteria codes

• PVS1: This is a missense variant.
• PS2: Two families are reported in the literature and the variant is present in maternal family members of the proband.
• PS3: There are no functional studies reported for this variant.
• PS1: No other variants resulting in the same amino acid change are reported.
• PP1: For Patient 2 in Krylova et al (PMID: 31669237), the healthy mother had similar heteroplasmy levels to the proband (PROBAND: 47% blood, 72% urine, 100% fibroblast; MOTHER: 45% blood, 78% urine, not done in fibroblasts). For patients 3 and 4 in Peverelli et al (PMID: 34177762), the only description of patient 4 is "maternal relative" of patient 3. Both individuals have the variant present at homoplasmy in blood. There is no mention of testing in family members.
• PM5: m.13379A>C (p.H348P) has been reported to be associated with LHON, however evidence did not meet criteria to be classified as pathogenic or likely pathogenic.
• PM6: Two families are reported in the literature and the variant is present in maternal family members of the proband.

Approved on: 2022-06-30

Published on: 2022-06-30