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]
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  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001005361.3(DNM2):c.1393C>T (p.Arg465Trp)

CA172098

7281 (ClinVar)

Gene: DNM2
Condition: centronuclear myopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 5181b063-b33d-441a-9219-309d92fe0501
Approved on: 2024-08-07
Published on: 2024-10-01

HGVS expressions

NM_001005361.3:c.1393C>T
NM_001005361.3(DNM2):c.1393C>T (p.Arg465Trp)
NC_000019.10:g.10798543C>T
CM000681.2:g.10798543C>T
NC_000019.9:g.10909219C>T
CM000681.1:g.10909219C>T
NC_000019.8:g.10770219C>T
NG_008792.1:g.85465C>T
ENST00000682285.1:n.1581C>T
ENST00000683738.1:n.1720C>T
ENST00000355667.11:c.1393C>T
ENST00000389253.9:c.1393C>T
ENST00000355667.10:c.1393C>T
ENST00000359692.10:c.1393C>T
ENST00000389253.8:c.1393C>T
ENST00000408974.8:c.1393C>T
ENST00000585892.5:c.1393C>T
ENST00000587329.1:n.157C>T
ENST00000587830.2:c.649C>T
ENST00000593220.1:n.542C>T
NM_001005360.2:c.1393C>T
NM_001005361.2:c.1393C>T
NM_001005362.2:c.1393C>T
NM_001190716.1:c.1393C>T
NM_004945.3:c.1393C>T
NM_001190716.2:c.1393C>T
NM_001005360.3:c.1393C>T
NM_001005362.3:c.1393C>T
NM_004945.4:c.1393C>T

Pathogenic

Met criteria codes 4
PS4 PS3 PP3 PP1_Strong
Not Met criteria codes 3
BA1 PM2 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 variant NM_001005361.3:c.1393C>T in DNM2 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 465 (p.Arg465Trp). The highest population minor allele frequency in gnomAD v4.1 is 0.000001695 (2/1180018 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The REVEL computational prediction analysis tool produced a score of 0.83, which is above the threshold necessary to apply PP3. This variant has been reported in at least six probands with confirmed centronuclear myopathy (PS4; PMID: 16227997, 19130742, 22613877, 26908122, 28740838, 34463354, 34595679). In addition, it segregated in five affected individuals in one family (PP1_Strong; PMID: 16227997). Functional studies have demonstrated that this variant increases GTPase activity compared to wildtype dynamin (PMIDs: 20529869, 26199319). Several knock-in mouse models with the variant have been created and show muscle defects, progressive atrophy and morphological abnormalities similar to those observed in human biopsies, and DNM2 reduction has been shown to rescue the phenotype in mice (PS3; PMIDs: 20858595, 30291191). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP3, PS4, PP1_Strong, PS3. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024)
Met criteria codes
PS4
This variant has been reported in six probands by Bitoun et al. 2005, who had confirmed centronuclear myopathy. This variant has also been reported in probands in at least six additional publications.
PS3
functional studies have demonstrated that this variant increases GTPase activity compared to wildtype dynamin (PMIDs: 20529869, 26199319). Several knock-in mouse models with the variant have been created and show muscle defects, progressive atrophy and morphological abnormalities similar to those observed in human biopsies, and DNM2 reduction has been shown to rescue the phenotype in mice (PMIDs: 20858595, 30291191).
PP3
The REVEL computational prediction analysis tool produced a score of 0.83, which is above the threshold necessary to apply PP3.
PP1_Strong
Family three from Bitoun et al. 2005 had five affected segregations reported, meeting PP1_Strong.
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The highest population minor allele frequency in gnomAD v4.1 is 0.000001695 (2/1180018 alleles) in the European (non-Finnish) population. (PM2_Supporting, BS1, and BA1 are not met)
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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