Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001005361.3(DNM2):c.1565G>A (p.Arg522His)

CA172101

158514 (ClinVar)

Gene: DNM2
Condition: centronuclear myopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d004ed75-6cb8-497c-8c90-c58b35cfa6c4
Approved on: 2025-04-14
Published on: 2025-06-23

HGVS expressions

NM_001005361.3:c.1565G>A
NM_001005361.3(DNM2):c.1565G>A (p.Arg522His)
NC_000019.10:g.10812271G>A
CM000681.2:g.10812271G>A
NC_000019.9:g.10922947G>A
CM000681.1:g.10922947G>A
NC_000019.8:g.10783947G>A
NG_008792.1:g.99193G>A
ENST00000681972.1:n.996G>A
ENST00000355667.11:c.1565G>A
ENST00000389253.9:c.1565G>A
ENST00000355667.10:c.1565G>A
ENST00000359692.10:c.1553G>A
ENST00000389253.8:c.1565G>A
ENST00000408974.8:c.1553G>A
ENST00000585892.5:c.1565G>A
ENST00000587830.2:c.839G>A
ENST00000590787.1:n.3064G>A
ENST00000590806.5:n.3753G>A
NM_001005360.2:c.1565G>A
NM_001005361.2:c.1565G>A
NM_001005362.2:c.1553G>A
NM_001190716.1:c.1565G>A
NM_004945.3:c.1553G>A
NM_001190716.2:c.1565G>A
NM_001005360.3:c.1565G>A
NM_001005362.3:c.1553G>A
NM_004945.4:c.1553G>A
More

Pathogenic

Met criteria codes 7
PS2 PS4 PP3 PP2 PM2_Supporting PS3_Supporting PP1_Moderate
Not Met criteria codes 16
BP5 BP3 BP4 BP1 PS1 PP4 PM6 PM1 PM4 PM5 PM3 BA1 BS2 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Congenital Myopathies VCEP
The NM_001005361.3:c.1565G>A variant in DNM2 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 522 (p.Arg522His). The variant is absent from gnomAD v4.1.0 meeting 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 REVEL computational prediction analysis tool gives a score of 0.892, which is above the threshold necessary to apply PP3. This variant has been reported in at least eight probands with centronuclear myopathy, of which two were identified to be de novo occurrences (PS2, PS4; PMIDs: 20227276, 29105112, 32826616; Baylor Genetics, GeneDx, Athena Diagnostics, ClinVar: SCV000807289.2, SCV000329752.6, SCV000841851.1; VCEP Internal data contributor). Additionally, the variant segregated with disease in 4 family members meeting PP1_Moderate (PMID: 20227276). Live correlative scanning ion conductance microscopy (SICM) and fluorescence confocal microscopy (FCM) showed that the p.Arg522His variant slows down the formation of clathrin-coated pits in skin fibroblasts from patients and in Cos-7 cells expressing corresponding dynamin mutants (PS3_Supporting, PMID: 31017801). In summary, the variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS2, PS4, PP1_Moderate, PS3_Supporting, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 4/14/2025
Met criteria codes
PS2
The variant was confirmed de novo in 2 probands with centronuclear myopathy (PMID: 32826616, Baylor Genetics, ClinVar: SCV000807289.2)
PS4
This variant has been reported in at least eight probands with centronuclear myopathy, of which two were identified to be de novo occurrences (PS2, PS4; PMIDs: 20227276, 29105112, 32826616; Baylor Genetics, GeneDx, Athena Diagnostics, ClinVar: SCV000807289.2, SCV000329752.6, SCV000841851.1; VCEP Internal data contributor).
PP3
The REVEL tool gives a score of 0.892.
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.
PM2_Supporting
The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting.
PS3_Supporting
Live correlative scanning ion conductance microscopy (SICM) and fluorescence confocal microscopy (FCM) showed that the p.Arg522His variant slows down the formation of clathrin-coated pits in skin fibroblasts from patients and in Cos-7 cells expressing corresponding dynamin mutants. It also affects the distribution of caveoli and reduce dorsal ruffling in human skin fibroblasts. (PMID: 31017801)
PP1_Moderate
The variant segregated with disease in 4 family members in 2 families (PMID: 20227276)
Not Met criteria codes
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
The REVEL tool gives a score of 0.892.
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting.
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting.
Curation History
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