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)
ClinVar Genomic variation as it relates to human health
NM_001005361.3(DNM2):c.1565G>A (p.Arg522His)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(10)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001005361.3(DNM2):c.1565G>A (p.Arg522His)
Variation ID: 158514 Accession: VCV000158514.49
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 10812271 (GRCh38) [ NCBI UCSC ] 19: 10922947 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 23, 2014 Oct 20, 2024 Nov 1, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001005361.3:c.1565G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005361.1:p.Arg522His missense NM_001005360.3:c.1565G>A NP_001005360.1:p.Arg522His missense NM_001005362.3:c.1553G>A NP_001005362.1:p.Arg518His missense NM_001190716.2:c.1565G>A NP_001177645.1:p.Arg522His missense NM_004945.4:c.1553G>A NP_004936.2:p.Arg518His missense NC_000019.10:g.10812271G>A NC_000019.9:g.10922947G>A NG_008792.1:g.99193G>A LRG_238:g.99193G>A LRG_238t1:c.1565G>A LRG_238p1:p.Arg522His P50570:p.Arg522His - Protein change
- R522H, R518H
- Other names
- -
- Canonical SPDI
- NC_000019.10:10812270:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| DNM2 | - | - |
GRCh38 GRCh37 |
1138 | 1238 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 8, 2013 | RCV000145903.7 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 26, 2020 | RCV000275646.31 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Nov 1, 2023 | RCV000552861.13 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 19, 2022 | RCV000679888.6 | |
|
See cases
|
Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 20, 2020 | RCV002252002.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 08, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Myopathy, centronuclear
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000193040.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
|
|
|
Pathogenic
(Dec 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000841851.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
|
Pathogenic
(Sep 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329752.6
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(May 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant centronuclear myopathy
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580687.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4, PM6, PM2_SUP, PP1, PP3
|
Number of individuals with the variant: 2
Sex: female
|
|
|
Pathogenic
(Sep 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant centronuclear myopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Baylor Genetics
Accession: SCV000807289.2
First in ClinVar: Sep 17, 2018 Last updated: Dec 11, 2022 |
Comment:
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 … (more)
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. (less)
|
|
|
Likely pathogenic
(Aug 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523767.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PS4, PM2, PM6, PP1
Clinical Features:
Tachycardia (present) , Scoliosis (present) , Muscular dystrophy (present) , Muscle weakness (present) , Increased body weight (present) , Abnormal skeletal morphology (present) , Movement … (more)
Tachycardia (present) , Scoliosis (present) , Muscular dystrophy (present) , Muscle weakness (present) , Increased body weight (present) , Abnormal skeletal morphology (present) , Movement disorder (present) , Abnormality of limbs (present) (less)
Geographic origin: Brazil
|
|
|
Pathogenic
(May 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021729.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease dominant intermediate B
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000640226.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
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). … (more)
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). Advanced 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 at Invitae 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. (less)
|
|
|
Pathogenic
(Jul 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249694.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Jan 06, 2016)
|
no assertion criteria provided
Method: literature only
|
Charcot-Marie-Tooth disease dominant intermediate B
Affected status: yes
Allele origin:
germline
|
Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174764.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
|
Comment:
Comment:
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.
Comment:
ACMG classification criteria: PS4, PM2, PM6, PP1
Comment:
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). Advanced 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 at Invitae 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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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)
Comment:
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.
Comment:
ACMG classification criteria: PS4, PM2, PM6, PP1
Comment:
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). Advanced 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 at Invitae 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| DNM2 mutations in Chinese Han patients with centronuclear myopathy. | Lin P | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2016 | PMID: 26908122 |
| Zebrafish as a Model to Investigate Dynamin 2-Related Diseases. | Bragato C | Scientific reports | 2016 | PMID: 26842864 |
| Centronuclear myopathies: genotype-phenotype correlation and frequency of defined genetic forms in an Italian cohort. | Fattori F | Journal of neurology | 2015 | PMID: 25957634 |
| Clinical, pathological, and genetic features of dynamin-2-related centronuclear myopathy in China. | Chen T | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2015 | PMID: 25501959 |
| Clinical and Pathological Features of Korean Patients with DNM2-Related Centronuclear Myopathy. | Park YE | Journal of clinical neurology (Seoul, Korea) | 2014 | PMID: 24465259 |
| Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy. | Böhm J | Human mutation | 2012 | PMID: 22396310 |
| Mild functional differences of dynamin 2 mutations associated to centronuclear myopathy and Charcot-Marie Tooth peripheral neuropathy. | Koutsopoulos OS | PloS one | 2011 | PMID: 22096584 |
| Expanding the clinical, pathological and MRI phenotype of DNM2-related centronuclear myopathy. | Susman RD | Neuromuscular disorders : NMD | 2010 | PMID: 20227276 |
Text-mined citations for rs587783595 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.