Variant: NM_001005361.3(DNM2):c.1678G>A (p.Glu560Lys)

CA10584608

246082 (ClinVar)

Gene: DNM2

Condition: centronuclear myopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: a9bd9d4c-d2fe-469a-9f52-eea34a6ea84e

Approved on: 2025-05-12

Published on: 2025-06-23

HGVS expressions

NM_001005361.3:c.1678G>A
NM_001005361.3(DNM2):c.1678G>A (p.Glu560Lys)
NC_000019.10:g.10819986G>A
CM000681.2:g.10819986G>A
NC_000019.9:g.10930662G>A
CM000681.1:g.10930662G>A
NC_000019.8:g.10791662G>A
NG_008792.1:g.106908G>A
ENST00000681972.1:n.1109G>A
ENST00000355667.11:c.1678G>A
ENST00000389253.9:c.1678G>A
ENST00000355667.10:c.1678G>A
ENST00000359692.10:c.1666G>A
ENST00000389253.8:c.1678G>A
ENST00000408974.8:c.1666G>A
ENST00000585892.5:c.1678G>A
ENST00000590787.1:n.3177G>A
ENST00000590806.5:n.3866G>A
NM_001005360.2:c.1678G>A
NM_001005361.2:c.1678G>A
NM_001005362.2:c.1666G>A
NM_001190716.1:c.1678G>A
NM_004945.3:c.1666G>A
NM_001190716.2:c.1678G>A
NM_001005360.3:c.1678G>A
NM_001005362.3:c.1666G>A
NM_004945.4:c.1666G>A

Likely Pathogenic

• Met criteria codes: PM6 PS3_Supporting PM2_Supporting PS4 PP2

• Not Met criteria codes: BP4 PP3

Expert Panel

Congenital Myopathies VCEP

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DNM2 Version 1.0.0

Evidence submitted by expert panel

Congenital Myopathies VCEP

The NM_001005361.3:c.1678G>A variant in DNM2 is a missense variant predicted to cause substitution of glutamate by lysine at amino acid 560 (p.Glu560Lys). This variant is absent from gnomAD v4.1.0 (PM2_supporting). DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The computational predictor REVEL gives a score of 0.686, which is neither above nor below the thresholds predicting a damaging or benign impact on DNM2 function (no codes met). This variant has been reported in 2 probands with centronuclear myopathy (PS4; 1.0 pt.; PMIDs: 19122038, 22396310). This variant has been identified as a suspected de novo occurrence in one individual with centronuclear myopathy (PM6; PMID: 22396310). Membrane fission/dissociation assay using incubated DNM2 protein showed notably increased fission activity but reduced dissociation efficiency for the mutant indicating that this variant impacts protein function (PS3_supporting; PMID: 26199319). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PM6, PS3_Supporting, PM2_Supporting, PP2 (ClinGen Congenital Myopathies VCEP Specifications Version 1.0.0; 5/12/2025).

Met criteria codes

• PM6: This variant has been identified as a suspected de novo occurrence in 1 proband (PM6; PMID: 22396310).
• PS3_Supporting: Membrane fission/dissociation assay using incubated DNM2 protein showed notably increased fission activity but reduced dissociation efficiency for the mutant indicating that this variant impacts protein function (PS3_supporting; PMID: 26199319).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_supporting). Coverage of the gene in the region this variant occurs is adequate.
• PS4: This variant has been reported in 2 probands with centronuclear myopathy (including type 1 fiber predominance and opthalmoparesis/ptosis) (PS4; 1.0 pt.; PMIDs: 19122038, 22396310).
• PP2: *DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). Z-score for missense variants in DNM2 in gnomAD v4.1.0 is 4.87.

Not Met criteria codes

• BP4: The computational predictor REVEL gives a score of 0.686, which is neither above nor below the thresholds predicting a damaging or benign impact on DNM2 function (no codes met). In-silico predictions are conflicting.
• PP3: The computational predictor REVEL gives a score of 0.686, which is neither above nor below the thresholds predicting a damaging or benign impact on DNM2 function (no codes met). In-silico predictions are conflicting.