Variant: m.10563T>C

CA250589

9706 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 9786cfa8-8c2e-4eca-b9f5-5523078781d7

Approved on: 2023-10-23

Published on: 2024-11-25

HGVS expressions

NC_012920.1:m.10563T>C
J01415.2:m.10563T>C
ENST00000361335.1:c.94T>C

Uncertain Significance

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: BS1 BP4 PS4 BA1 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.10563T>C (p.C32R) variant in MT-ND4L has not been reported in individuals with primary mitochondrial disease to our knowledge. The computational predictors APOGEE1 and APOGEE2 produce conflicting evidence regarding the predicted functional impact of this variant with raw scores of 0.42 (neutral) and 0.840 (likely pathogenic), respectively (Min=0, Max=1). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). 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 October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).

Not Met criteria codes

• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: The m.10563T>C (p.C32R) variant in MT-ND4L has not been reported in individuals with primary mitochondrial disease to our knowledge (PS4_not met).
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: The computational predictors APOGEE1 and APOGEE2 produce conflicting evidence regarding the predicted functional impact of this variant with raw scores of 0.42 (neutral) and 0.840 (likely pathogenic), respectively (Min=0, Max=1; PP3_not met).