NM_001005361.3:c.1565G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2_SupportingPS4PS2PP2PP3PP1_ModeratePS3_Supporting

This summary comes from the ClinGen Evidence Repository: 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 LINK:https://erepo.genome.network/evrepo/ui/classification/CA172101/MONDO:0018947/148

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DNM2
NM_001005361.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11U:1

Conservation

PhyloP100: 10.0

Publications

29 publications found

Variant links:

Genes affected

DNM2 (HGNC:2974): (dynamin 2) Dynamins represent one of the subfamilies of GTP-binding proteins. These proteins share considerable sequence similarity over the N-terminal portion of the molecule, which contains the GTPase domain. Dynamins are associated with microtubules. They have been implicated in cell processes such as endocytosis and cell motility, and in alterations of the membrane that accompany certain activities such as bone resorption by osteoclasts. Dynamins bind many proteins that bind actin and other cytoskeletal proteins. Dynamins can also self-assemble, a process that stimulates GTPase activity. Five alternatively spliced transcripts encoding different proteins have been described. Additional alternatively spliced transcripts may exist, but their full-length nature has not been determined. [provided by RefSeq, Jun 2010]

DNM2 Gene-Disease associations (from GenCC):

autosomal dominant centronuclear myopathy
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease dominant intermediate B
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
autosomal dominant Charcot-Marie-Tooth disease type 2M
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
fetal akinesia-cerebral and retinal hemorrhage syndrome
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
hereditary spastic paraplegia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DNM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS2

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM2	NM_001005361.3 link	c.1565G>A	p.Arg522His	missense_variant	Exon 15 of 21	ENST00000389253.9	NP_001005361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM2	ENST00000389253.9 link	c.1565G>A	p.Arg522His	missense_variant	Exon 15 of 21	5	NM_001005361.3	ENSP00000373905.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447522

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719044

African (AFR)

AF:

0.00

AC:

AN:

33194

American (AMR)

AF:

0.00

AC:

AN:

42202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25820

East Asian (EAS)

AF:

0.00

AC:

AN:

39140

South Asian (SAS)

AF:

0.00

AC:

AN:

84812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51954

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104796

Other (OTH)

AF:

0.00

AC:

AN:

59854

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 04, 2019

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in association with centronuclear myopathy in published literature (Susman et al., 2010; Chen et al., 2015); Published functional studies demonstrate that R522H impairs protein interaction with microtubules and results in reduced clathrin-mediated endocytosis (Koutsopoulos et al., 2011; Bragato et al., 2016); Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; A diffferent missense change at this residue (R522C) has been reported in the Human Gene Mutation Database in association with CNM (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26908122, 22096584, 26842864, 20227276, 25501959, 27363342, 29105112, 28357410, 31017801, 32826616) -

May 26, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 07, 2017

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant centronuclear myopathy

Pathogenic:3

Sep 01, 2017

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 16-year-old female with centronuclear myopathy on muscle biopsy; proximal muscle weakness, facial weakness, fatigue, varus foot, waddling gait. -

Nov 07, 2022

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2-PM6, PP5, PP3 -

May 19, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Centronuclear myopathy

Pathogenic:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2025

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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 -

Charcot-Marie-Tooth disease dominant intermediate B

Pathogenic:1Uncertain:1

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 522 of the DNM2 protein (p.Arg522His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with centronuclear myopathy (PMID: 20227276, 22396310, 24465259, 25501959, 25957634, 26908122). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 158514). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNM2 protein function. Experimental studies have shown that this missense change affects DNM2 function (PMID: 22096584, 26842864). For these reasons, this variant has been classified as Pathogenic. -

See cases

Pathogenic:1

Aug 20, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4, PM2, PM6, PP1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

.;.;.;D;.;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.3

M;.;M;M;.;.

PhyloP100

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.4

.;.;D;.;D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

.;.;D;.;D;.

Sift4G

Uncertain

0.018

D;D;D;D;D;D

Polyphen

0.12, 1.0

.;B;.;D;.;.

Vest4

0.71

MutPred

0.88

Loss of MoRF binding (P = 0.0101);.;Loss of MoRF binding (P = 0.0101);Loss of MoRF binding (P = 0.0101);.;.;

MVP

0.91

MPC

2.3

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.9

Varity_R

0.68

gMVP

0.91

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over