Variant: NM_000252.3(MTM1):c.1353G>A (p.Gln451=)

CA271787

158923 (ClinVar)

Gene: MTM1

Condition: centronuclear myopathy

Inheritance Mode: X-linked inheritance

UUID: e8bd73b1-cdb8-4575-bd65-f890ba644dd5

Approved on: 2025-01-13

Published on: 2025-03-27

HGVS expressions

NM_000252.3:c.1353G>A
NM_000252.3(MTM1):c.1353G>A (p.Gln451=)
NC_000023.11:g.150659756G>A
CM000685.2:g.150659756G>A
NC_000023.10:g.149828229G>A
CM000685.1:g.149828229G>A
NC_000023.9:g.149578887G>A
NG_008199.1:g.96183G>A
ENST00000684910.1:c.*886G>A
ENST00000685439.1:c.1008G>A
ENST00000685944.1:c.1353G>A
ENST00000686212.1:n.955G>A
ENST00000687215.1:c.*1108G>A
ENST00000688152.1:c.*797G>A
ENST00000688403.1:c.609G>A
ENST00000689314.1:c.1398G>A
ENST00000689694.1:c.1353G>A
ENST00000689810.1:c.*1002G>A
ENST00000690282.1:c.609G>A
ENST00000690351.1:c.*1005G>A
ENST00000691232.1:c.1008G>A
ENST00000691482.1:n.2368G>A
ENST00000691686.1:c.1261-615G>A
ENST00000691851.1:c.1053+9855G>A
ENST00000692015.1:c.1140G>A
ENST00000692638.1:c.*1151G>A
ENST00000692852.1:c.1164G>A
ENST00000692915.1:c.*1499G>A
ENST00000370396.7:c.1353G>A
ENST00000306167.11:n.1220G>A
ENST00000370396.6:c.1353G>A
NM_000252.2:c.1353G>A
NM_001376906.1:c.1353G>A
NM_001376907.1:c.1242G>A
NM_001376908.1:c.1353G>A

Likely Pathogenic

• Met criteria codes: PP3 PM2_Supporting PS4_Moderate PM6

• Not Met criteria codes: BA1 BS1 BP4 BP1 PP2

Expert Panel

Congenital Myopathies VCEP

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MTM1 Version 1.0.0

Evidence submitted by expert panel

Congenital Myopathies VCEP

The NM_000252.3:c.1353G>A variant in MTM1 is a synonymous variant (p.Gln451=) located near the canonical donor site of intron 12. The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. The silent variant is predicted to impact splicing by SpliceAI (PP3). This variant has been reported in at least three probands, one with myotubular myopathy, one with congenital myopathy and abnormal muscle biopsy, and another with neonatal hypotonia. One of the three was a de novo occurrence with unconfirmed parental relationships (PS4_Moderate, PM6; PMID: 10790201; LabCorp, ClinVar: SCV001391223.5). In summary, the variant meets the criteria to be classified as likely pathogenic for X-linked centronuclear myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Moderate, PM6, PM2_Supporting, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 1/13/2025).

Met criteria codes

• PP3: This variant is located near the the canonical donor site of intron 12 and is predicted to lead to abnormal splicing. The SpliceAI score was 0.87.
• PM2_Supporting: This variant was absent from gnomAD v4 meeting PM2_Supporting
• PS4_Moderate: This variant has been reported in at least three probands, one with myotubular myopathy, one with congenital myopathy and abnormal muscle biopsy, and another with neonatal hypotonia (PMID: 10790201; LabCorp, ClinVar: SCV001391223.5)
• PM6: The variant was reported to be de novo in a proband (LabCorp, ClinVar: SCV001391223.5)

Not Met criteria codes

• BA1: This variant was absent from gnomAD v4 meeting PM2_Supporting
• BS1: This variant was absent from gnomAD v4 meeting PM2_Supporting
• BP4: The variant is predicted to impact splicing.
• BP1: Both missense and truncating variants in MTM1 are disease-causing.
• PP2: MTM1 is not a gene that is constrained for missense variation. Hence PP2 is not applicable.