Variant: NC_012920.1:m.5523T>G

CA345912

155882 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 79ec063d-fa82-46b9-84f4-afe2d73c6705

Approved on: 2024-05-13

Published on: 2024-12-04

HGVS expressions

NC_012920.1:m.5523T>G
J01415.2:m.5523T>G

Uncertain Significance

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: PM6 PS2 PS3 PS4 PP1 PP3

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.5523T>G variant in MT-TW has been reported in one individual with primary mitochondrial disease to date (PMID: 19349200). This was a boy with Leigh syndrome spectrum, hearing loss, and pigmentary retinopathy. The variant was present at 66% heteroplasmy in blood. There was no information provided on family member testing. There are no other individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is pathogenic (80.9 percentile) but HmtVAR predicts it to be neutral with a score of 0.25. There are no cybrids, single fiber studies, or other functional assays 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in the Mitomap (0/611634), gnomAD (0/56434), and Helix ( 0/195893) databases as of May 13, 2024.

Not Met criteria codes

• PM6: The m.5523T>G variant in MT-TW has been reported in one individual with primary mitochondrial disease to date (PMID: 19349200). This was a boy with Leigh syndrome spectrum, hearing loss, and pigmentary retinopathy. The variant was present at 66% heteroplasmy in blood. There was no information provided on family member testing. There are no other individuals reported with de novo occurrences of this variant to our knowledge.
• PS2: The m.5523T>G variant in MT-TW has been reported in one individual with primary mitochondrial disease to date (PMID: 19349200). This was a boy with Leigh syndrome spectrum, hearing loss, and pigmentary retinopathy. The variant was present at 66% heteroplasmy in blood. There was no information provided on family member testing. There are no other individuals reported with de novo occurrences of this variant to our knowledge.
• PS3: No functional studies were found in our review of the literature.
• PS4: The m.5523T>G variant in MT-TW has been reported in one individual with primary mitochondrial disease to date (PMID: 19349200). This was a boy with Leigh syndrome spectrum, hearing loss, and pigmentary retinopathy. The variant was present at 66% heteroplasmy in blood. There was no information provided on family member testing. There are no other individuals reported with de novo occurrences of this variant to our knowledge.
• PP1: No family information was given for the one patient reported in the literature (PMID 19349200).
• PP3: In-silico predictors were conflicting: MitoTip, 0.809 “Likely Pathogenic”; HmtVar 0.25 “Likely Polymorphic”.